TW202102485A - Anthelmintic aza-benzothiophene and aza-benzofuran compounds - Google Patents

Abstract

This invention provides for compounds of the formula: wherein the variables are defined herein, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, compositions comprising these compounds, and method for the treatment, control or prevention of a parasitic infestation or infection in an animal in need thereof by administering an effective amount of these compounds to said animal.

Description

Deworming aza-benzothiophene and aza-benzofuran compounds

This patent application is about novel antiparasitic compounds; compositions containing these compounds; their preparation process; and methods of using these compounds to control parasites that harm animals.

Animals such as mammals and birds are usually susceptible to parasites. These parasites may be surface parasites, such as fleas and ticks. Animals and humans also suffer from endoparasitic infections, including, for example, helminthiasis, which is most often caused by a group of parasites described as nematodes or roundworms. These parasites cause severe economic losses to pigs, sheep, horses and cattle, and affect companion animals (such as cats and dogs) and poultry. Other parasites include those that exist in the gastrointestinal tract of animals and humans, such as Ancylostoma , Necator , Ascaris , Strongyloides , Trichinella , and Trichinella (Capillaria), bow roundworm (Toxocara), roundworm C. elegans (Toxascaris), whipworm (Trichuris) and live intestinal nematodes (Enterobius). Other parasites present in the blood or other tissues and organs include strongyloides such as filarial and extraintestinal stages and Trichinella spiralis.

One type of internal parasite that seriously harms mammals is Dirofilaria immitis , also known as Heartworm. Other filarial endoparasites include Dirofilaria repens and Dirofilaria honkongensis , which can also infect humans. The most common hosts are dogs and cats, but other mammals such as ferrets and raccoons may also be infected. Heartworms go through several life stages before they become adults that infect the pulmonary arteries of host mammals. Insects need mosquitoes as intermediate hosts to complete their life cycle. The period between the initial infection when a dog is bitten by a mosquito and the maturity of the worm into an adult that survives in the heart and pulmonary arteries is six to seven months in dogs, and is called the "incubation period." L3 larvae migrate to the tip of the mosquito’s mouth (lips) during the mosquito’s blood intake, leave the mosquito and stay on the dog’s skin, and then migrate to the host through the bite wound. Most L3 larvae morph into stage IV larvae (L4) in the canine subcutaneous tissue within 1 to 3 days after infection. Subsequently, these fourth stage larvae migrate to the chest and abdominal muscles, and metamorphose into the fifth stage (L5, immature adult) 45 to 60 days after infection. Between 75 and 120 days after infection, these immature heartworms then enter the bloodstream and are carried through the heart to reside in the pulmonary arteries. About seven months after the infection, the adult Heartworm canis reaches maturity and reproduces sexually in the pulmonary artery and right ventricle. The length of an adult male is about 15 cm, and the length of a female is about 25 cm, and its general life span as an adult is calculated to be about 5 years.

Heartworm infection is a serious and life-threatening disease. Canine heartworm infection is preventable, and preventive treatment is preferred in heartworm endemic areas. Insecticides (such as melarsomine dihydrochloride) to treat mature heartworm infections are expensive and can cause serious adverse side effects. Therefore, drugs that interrupt larval development by monthly administration are widely used To prevent. The goal of commercially available canine heartworm preventive therapy is to prevent the parasites from developing into adult heartworms by interrupting the life cycle of heartworms after infection.

Macrolides (ML, such as ivermectin, eprinomectin, milbemycin oxime, moxidectin and selamectin) are The most commonly used chemopreventive agent, and it is administered every month or at six-month intervals. These drugs are effective against the third-stage larva (L3) of the infective heartworm (L3) and the fourth-stage larva (L4) in maturity left by mosquitoes. When administered monthly, ML kills L3 and L4 larvae obtained in the previous 30 days, and thus prevents diseases caused by adults. ML can also be used monthly in infected dogs to inhibit adult reproduction and remove microfilaria, thereby reducing transmission and gradually causing adult consumption ( Vet. Parasitol. October 24, 2005 133(2-3) 197- 206).

In recent years, an increase in the number of lack of efficacy (LOE) conditions has been reported, in which dogs still develop mature heartworm infections despite receiving preventive doses of macrolide drugs every month. For example, Atkins et al. ( Vet. Parasitol. 206 (2014) 106-113) recently reported an increase in the number of dogs that tested positive for heartworm antigens while receiving heartworm prophylactic drug treatment, indicating that some Heartworm Preventive Resistance. Is it Possible, Vol. 37. Bulletin of the American Heartworm Society, p. 5. The Heartworm Preventive Resistance. Is it Possible (American Heartworm Society, 2010. Heartworm Preventive Resistance. Is it Possible, Vol. 37. Bulletin of the American Heartworm Society, page 5.) . Therefore, there is a continuing need to develop novel repellents with improved activity against heartworm and other endoparasites.

WO 2017/178416 A1 provides pyrazolopyrimidine derivatives for controlling, treating and/or preventing worms. WO 2018/197401 A1 provides bicyclic pyrazole derivatives for controlling, treating and/or preventing worms. WO 2018/087036 A1 provides quinolinone-3-formamide derivatives for controlling, treating and/or preventing worms. WO 2019/025341 provides quinoline compounds for the treatment, control and/or prevention of helminth infections, and WO 2019/002132 A1 provides azaquinone derivatives for the control, treatment and/or prevention of helminths. All such publications belong to Bayer Animal Health GmbH and are incorporated herein by reference in their entirety.

Recently, WO 2020/014068 A1 (which is incorporated herein by reference) describes an anthelmintic heterocyclic compound found to be active against Heartworm canis.

It is clearly noted that the quotation or identification of any document in this application is not an admission that such documents can be obtained as prior art in this specification. Any aforementioned application, and all documents cited in or during its examination ("application cited documents"), and all documents cited or referenced in the application cited documents, and all documents cited or referenced in this article ( "Citations in this article"), and all the documents cited or referenced in this article, as well as any manufacturer's instructions, manuals, and product instructions for any product mentioned in this article or any document incorporated into this article by reference And the product introduction is incorporated into this article by reference, and can be used in the practice of this manual.

This application provides novel anthelmintic and antiparasitic heterocyclic compounds with improved activity against endoparasites and ectoparasites. This application also relates to compositions containing these compounds, and methods and uses of these compounds for eradicating, controlling and preventing parasite infestation and/or infection in animals (including humans). These compounds can be administered to animals, specifically mammals, fish, and birds to prevent or treat parasitic infections.

其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽，其中變數R¹ 、R³ 、R¹⁰ 、Y¹ 、Y² 、Y³ 、X、L、W、Z、Y^1' 、Y^2' 、Y^3' 、Y^4' 、Y^5' 、Y^6' 、a及q如本文所定義，且虛線鍵(

)表示單鍵或雙鍵。One aspect of the present invention includes a compound of formula (I):

Its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, in which the variables R ¹ , R ³ , R ¹⁰ , Y ¹ , Y ² , Y ³ , X, L, W , Z, Y ^1' , Y ^2' , Y ^3' , Y ^4' , Y ^5' , Y ^6' , a and q are as defined herein, and the dashed bond (

) Represents a single bond or a double bond.

The present invention also includes a veterinarily acceptable composition comprising a compound of formula (I) and a veterinarily acceptable carrier, and a method for controlling parasites including helminths, the method comprising administering to animals in need The compound or its veterinarily acceptable composition. An embodiment of the present invention also includes the use of the compound of formula (I) for eradicating, controlling and preventing parasite infestation and/or infection in animals. The compounds of the present invention can be administered to animals, in particular, to mammals, fish and birds to prevent or treat parasitic infections.

The compound and the composition containing the compound effectively treat and prevent internal parasites in mammals, fish and birds, and in particular cats, dogs, horses, chickens, pigs, sheep and cattle, with the purpose of Make these hosts essentially get rid of internal parasites.

In one embodiment, the compound of formula (I) and the composition containing the compound are substantially effective against endoparasites such as filarial worms (such as heartworms), hookworms, whipworms, and roundworms of the digestive tract of animals and humans. In certain embodiments, the compounds of formula (I) and compositions containing these compounds are effective against heartworm (heartworm) isolates that are less sensitive to treatment with macrolides. In another embodiment, the compounds and compositions of the present invention are effective in treating and preventing nematode infections in animals that are less sensitive to treatment with commercially available or known active agents.

In one embodiment, this specification includes a combination of a compound of formula (I) and at least a second active agent, which can broaden the scope of protection provided to animals against endoparasites and/or ectoparasites.

Another embodiment includes a method for treating and/or preventing parasitic infection and/or infestation in an animal, which comprises administering a compound of formula (I) to the animal. Another embodiment includes the use of the compound of formula (I) for the treatment and/or prevention of parasitic infection and/or infestation in animals, and the preparation of the compound of formula (I) for the treatment and/or prevention of parasites in animals Use in infectious agents.

Therefore, the present invention includes the following non-limiting examples: (a) The compound of formula (I) or its pharmaceutically or veterinarily acceptable salt, which is an active endoparasitic agent and in some cases is also active against ectoparasites; (b) A veterinary combination comprising a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt in a parasiticidal effective amount and a pharmaceutically or veterinarily acceptable carrier or diluent Thing (c) A compound of formula (I) or its pharmaceutically or veterinarily acceptable salt and one or more other active agents (that is, active ingredients not covered by formula (I)) containing a parasiticidal effective amount, and A veterinary composition with a combination of pharmaceutically or veterinarily acceptable carriers or diluents; (d) A method for treating parasitic infestation/infection in or on the body of an animal, which comprises administering to an animal in need an effective amount of a compound of formula (I) or its pharmacological or veterinary Acceptable salts and optionally one or more other active agents (ie, active ingredients not covered by formula (I)); (e) A method for preventing parasitic infestation/infection in animals, which comprises administering to animals in need of a parasitic effective amount of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt And optionally one or more other active agents (that is, active ingredients not covered by formula (I)); (f) The use of the compound of formula (I) or its pharmaceutically or veterinarily acceptable salt to treat or prevent parasitic infection and possible parasitic infestation in animals; (g) The use of the compound of formula (I) or its pharmaceutically or veterinarily acceptable salt in the manufacture of veterinary medicines for the treatment or prevention of parasitic infections in animals; and (h) The method used to prepare the compound of formula (I).

Therefore, one of the objectives of the present invention is that the present invention does not cover any previously known products, processes for preparing the products, or methods for using the products, so that the applicant has the right and hereby discloses the disclaimer of any previously known products, processes or methods statement. In addition, it should be noted that the present invention does not intend to cover any product that does not comply with the written instructions and implementation requirements of USPTO (35 USC §112, first paragraph) or EPO (EPC Chapter 83) within the scope of the present invention. The process or method of using the product entitles the applicant to have the right to and hereby disclose any disclaimer of any previously described product, the process of preparing the product, or the method of using the product. It may be advantageous for the practice of the present invention to follow Art. 53(c) EPC and Rule 28(b) and (c) EPC. Expressly waive all rights of any embodiment of the subject matter of any granted patent of the applicant in the pedigree of this application or in any other pedigree or any third party in any previously applied application. Nothing in this article should be taken as a promise.

The term "compound of formula (I)" includes any stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof.

These and other examples are disclosed in the following [Embodiments] or are obvious from the following [Embodiments] and are encompassed in the following [Embodiments].

Definition: It should be noted that in the present invention and especially in the scope of patent application and/or paragraphs, terms such as "comprises/comprised/comprising" and the like may have the meanings assigned to them in the U.S. Patent Law; for example, It can mean "includes/included/including" and the like; and terms such as "consisting essentially of/consists essentially of" have the meaning assigned to it in the U.S. Patent Law, for example It makes the elements need not be explicitly listed, but excludes elements found in the prior art or affecting the basic or novel features of the present invention.

Unless otherwise specified, the terms used herein will have their usual meanings in the art. The organic moiety mentioned in the definition of the variable of a compound (for example a compound of formula (I)) is similar to the term halogen, which is a collective term for individual lists of individual group members, fluorine, chlorine, bromine and iodine relative to halogen. In each case, the prefixes C _n -C _m indicate the number of possible carbon atoms in a group from an integer n to another integer m.

In this specification and the scope of the patent application, the term "including (but not limited to)" is equivalent to "including".

The term "optionally substituted" means a group that is optionally substituted with one or more of the following: halogen, hydroxyl, carboxyl, acyl, acyloxy, amine, alkyl- or dialkylamino group , Amide, arylamino, alkoxy, aryloxy, nitro, cyano, azide, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, Sulfonyl, sulfamyl, ester, phosphinyl, phosphinyl, phosphinyl, phosphine, thioester, thioether, acid halide, acid anhydride, oxime, hydrazine, carbamate, phosphonic acid , Phosphate, phosphonate, aryl and heteroaryl, or as known to those skilled in the art, such as Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 1999 (here Incorporate by reference) any other feasible functional groups taught in) that are unprotected or protected as needed that will not inhibit the biological activity of the compounds of this specification. For the avoidance of doubt, "optionally substituted alkyl" includes haloalkyl.

Unless otherwise specified, "alkyl" alone or in combination with heteroatoms (such as alkoxy, sulfanyl, alkylamino and the like) means saturated linear, branched, primary, secondary, or tertiary Grade hydrocarbons include those alkyl groups having 1 to 12 atoms. In some embodiments, the alkyl group will include C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ or C ₁ -C ₃ alkyl. Examples of C ₁ -C ₁₀ alkyl groups include (but are not limited to) methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl , 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1-Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3 ,3-Dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl 1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl and isomers thereof. C ₁ -C ₄ alkyl means for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethyl Ethyl.

Cyclic alkyl groups may be referred to as "cycloalkyl groups" and include those cyclic alkyl groups having 3 to 10 carbon atoms having single or multiple fused rings. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

A carbocyclic group is a cyclic group composed exclusively of carbon. Carbocyclic groups include both aromatic rings (such as phenyl) and non-aromatic rings (such as cycloalkyl rings, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), and include These carbocyclic groups having 3 to 14 carbon atoms and having single or multiple fused rings.

The term "alkenyl" refers to both straight and branched carbon chains with at least one carbon-carbon double bond. In some embodiments, the alkenyl group may include a C ₂ -C ₁₂ alkenyl group. In other embodiments, the alkenyl group includes C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ , C ₂ -C ₄ or C ₃ -C ₄ alkenyl. In one embodiment of alkenyl, the number of double bonds is 1 to 3; in another embodiment of alkenyl, the number of double bonds is one. Depending on the position of the alkenyl moiety on the molecule, it also covers other ranges of carbon-carbon double bonds and the number of carbons. "Alkenyl" may include more than one double bond in the chain. Examples of alkenyl or specific ranges thereof include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-methyl-vinyl, 1-butenyl, 2-butenyl, 3-butenyl Alkenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2 -Pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3 -Butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl- 2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5 -Hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1 -Methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3- Pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2- Methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-di Methyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl , 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl -3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3 ,3-Dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1 -Ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-tri Methyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2- Allyl.

"Alkynyl" refers to both straight and branched carbon chains with at least one carbon-carbon bond. In one embodiment of alkynyl, the number of parametric bonds is 1 to 3; in another embodiment of alkynyl, the number of parametric bonds is one. In some embodiments, the alkynyl group includes 2 to 12 carbon atoms. In other embodiments, alkynyl groups may include C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ or C ₂ -C ₄ alkynyl groups. Depending on the position of the alkenyl moiety on the molecule, other ranges of carbon-carbon bond and the number of carbons are also covered. For example, the term "C ₂ -C ₁₀ alkynyl" as used herein refers to a linear or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing at least one parametric bond, such as ethynyl, prop- 1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl , N-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yl Alkyn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3 -Yl, 3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1 -Alkyn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2 -Yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn -3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl, 4-methyl Pent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and similar groups.

The term "haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more halogen atoms. For example, C ₁ -C ₄ haloalkyl groups include (but are not limited to) chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, Chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-Trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2 , 2-Trichloroethyl, pentafluoroethyl and similar groups. The term "fluoroalkyl" as used herein refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms, such as difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl , 2,2-Difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl or pentafluoroethyl.

The term "haloalkenyl" refers to an alkenyl group as defined herein substituted with one or more halogen atoms.

The term "haloalkynyl" refers to an alkynyl group as defined herein substituted with one or more halogen atoms.

The term "alkoxy" refers to alkyl -O- , where alkyl is as defined above. Similarly, the terms "alkenyloxy", "alkynyloxy", "haloalkoxy", "haloalkenyloxy", "haloalkynyloxy", "cycloalkoxy", "cycloalkenyloxy" , "Halocycloalkoxy" and "halocycloalkenyloxy" respectively refer to the groups alkenyl- O- , alkynyl- O- , haloalkyl -O- , haloalkenyl- O- , haloalkynyl -O- , cycloalkyl -O- , cycloalkenyl- O- , halocycloalkyl- O- and halocycloalkenyl- O- , among which alkenyl, alkynyl, haloalkyl, haloalkenyl, halo Alkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, and halocycloalkenyl are as defined above. Examples of C ₁ -C ₆ alkoxy include (but are not limited to) methoxy, ethoxy, OCH ₂ -C ₂ H ₅ , OCH(CH ₃ ) ₂ , n-butoxy, OCH(CH ₃ )- C ₂ H ₅ , OCH ₂ -CH(CH ₃ ) ₂ , OC(CH ₃ ) ₃ , n-pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy , 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexyloxy, 1-methyl Pentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy , 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy Oxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-Ethyl-2-methylpropoxy and similar groups.

The term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring or multiple fused rings. Aryl groups include, but are not limited to, phenyl, biphenyl and naphthyl. In some embodiments, aryl groups include tetrahydronaphthyl, phenylcyclopropyl, and indenyl. Aryl groups may be unsubstituted or substituted with one or more moieties selected from the group consisting of halogen, cyano, nitro, hydroxyl, mercapto, amine, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , Haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, Cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl, alkene Alkylsulfinyl, alkynylsulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfinyl, alkenylsulfinyl, alkyne Sulfonyl, haloalkylsulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, -SF ₅ , alkylamino, alkenylamino, alkynylamino, di(alkyl) Amino, di(alkenyl)amino, di(alkynyl)amino or trialkylsilyl group.

The term "aralkyl" refers to _{an aryl group bonded to the parent compound via a diradical alkylene bridge (-CH 2} -) _n , where n is 1 to 12, and where "aryl" is as defined above.

The term "heteroaryl" refers to having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and having one or more oxygen, nitrogen and sulfur heteroatoms, preferably 1 to 4 heteroatoms or A monovalent aromatic group of 1 to 3 heteroatoms. Nitrogen and sulfur heteroatoms can be oxidized depending on the situation. Heteroaryl groups will generally include 5- or 6-membered aromatic rings. Such heteroaryl groups may have a single ring (for example, pyridyl or furyl) or multiple fused rings, with the restriction that the point of attachment is connected via heteroaryl ring atoms. Examples of heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinolinyl, Furanyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl, benzothienyl, imidazo Pyridyl, imidazopyrimidinyl or pyrrolopyrimidinyl. The heteroaryl ring may be unsubstituted or substituted with one or more moieties as described above for the aryl group.

The term "heterocyclyl", "heterocyclic" or "heterocyclic" refers to the completeness of having one or more oxygen, sulfur or nitrogen heteroatoms, preferably 1 to 4 or 1 to 3 heteroatoms in the ring A saturated or unsaturated cyclic group, such as a 3-membered to 7-membered monocyclic ring system, a 7-membered to 11-membered bicyclic ring system, or a 10-membered to 15-membered tricyclic ring system. Nitrogen and sulfur heteroatoms may be oxidized depending on the situation, and nitrogen heteroatoms may be quaternary ammonium depending on the situation. The heterocyclyl group can be attached at any heteroatom or carbon atom of the ring or ring system, and can be unsubstituted or substituted with one or more moieties as described above for aryl groups.

Exemplary monocyclic heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, Pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolinyl, isothiazole Group, isothiazolidinyl, furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-side oxypiperazinyl, 2-side oxypiperidinyl, 2-side Oxypyrrolidinyl, 2-side oxyazinyl, azinyl, 4-piperidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropiperanyl, morpholinyl, Thimorpholinyl, Thimorpholinyl sulfide, Thimorpholinyl sulfide, 1,3-dioxolane and tetrahydro-1,1-di-side oxythiophene, triazolyl, triazinyl And similar groups.

Exemplary bicyclic heterocyclic groups include (but are not limited to) indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinoline Group, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopiperanyl, indolazinyl, benzofuranyl, chromonyl, coumarinyl, benzopiper Pyryl, oxolinyl, quinolinyl, indazolyl, pyrrolopyridyl, furopyridyl (such as furo[2,3-c]pyridyl, furo[3,2-b]pyridyl Or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4- pendant oxy-quinazolinyl), tetrahydro Quinolinyl and similar groups.

Bicyclic and tricyclic carbocyclic or heterocyclic ring systems include spiro ring systems in which at least two of the rings in the system are connected via a single carbon atom. The spirocyclic ring system will include a combination of 3- to 8-membered carbocyclic and/or heterocyclic ring systems attached at a common carbon atom. Therefore, a spirocyclic ring system can include all combinations of a 3-membered ring bonded to another 3-membered ring (carbocyclic or heterocyclic) to an 8-membered ring bonded to another 8-membered ring and different ring sizes in between. The heterocyclic component of the spirocyclic ring system will include one or two heteroatoms selected from N, O or S.

The term "alkylthio" refers to alkyl- S- , where "alkyl" is as defined above. In some embodiments, the alkyl component of the alkylthio group will include a C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ or C ₁ -C ₃ alkyl group. For example, C ₁ -C ₄ alkylthio includes (but is not limited to) methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio.

Similarly, the terms "haloalkylthio", "cycloalkylthio", and "halocycloalkylthio" refer to the groups -S-haloalkyl, -S -cycloalkyl, and -S-halocycloalkane, respectively Group, wherein the terms "haloalkyl", "cycloalkyl" and "halocycloalkyl" are as defined above.

The term "alkylsulfinyl" refers to the group alkyl-S(=0)-, where "alkyl" is as defined above. In some embodiments, the alkyl component of the alkylsulfinyl group will include C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₄ or C ₁ -C ₃ alkyl. Examples include (but are not limited to) -SO-CH ₃ , -SO-C ₂ H ₅ , n-propylsulfinyl, 1-methylethylsulfinyl, n-butylsulfinyl, 1- Methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, n-pentylsulfinyl, 1-methylbutylsulfinyl Sulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl Sulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, 1-methylpentylsulfinyl, 2-methyl Pentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethyl Butylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3 ,3-Dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl , 1,2,2-Trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl.

Similarly, the terms "alkenylsulfinyl", "alkynylsulfinyl", "haloalkylsulfinyl", "haloalkenylsulfinyl" and "haloalkynylsulfinyl" '' refers to the group alkenyl -S(=O)-, alkynyl-S(=O)- and haloalkyl-S(=O)-, haloalkenyl-S(=O)- and haloalkynyl -S(=O)-, where the terms "alkenyl", "alkynyl", "haloalkyl", "haloalkenyl" and "haloalkynyl" are as defined above.

The term "alkylsulfonyl" refers to the group alkyl-S(=0) _2- , where the term "alkyl" is as defined above. In some embodiments, the alkyl component of the alkylsulfonyl group will include C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ or C ₁ -C ₄ alkyl . Examples include (but are not limited to) -SO ₂ -CH ₃ , -SO ₂ -C ₂ H ₅ , n-propylsulfonyl, -SO ₂ -CH(CH ₃ ) ₂ , n-butylsulfonyl, 1- Methylpropylsulfonyl, 2-methylpropylsulfonyl, -SO ₂ -C(CH ₃ ) ₃ , n-pentylsulfonyl, 1-methylbutylsulfonyl, 2-methyl Butylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 2,2-dimethylpropane Sulfonyl, 1-ethylpropylsulfonyl, n-hexylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl , 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-Dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2 -Ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropyl Sulfonyl or 1-ethyl-2-methylpropylsulfonyl and similar groups.

The terms "alkenylsulfonyl", "alkynylsulfonyl", "haloalkylsulfonyl", "haloalkenylsulfonyl" and "haloalkynylsulfonyl" refer to the group alkenyl- S(=O) ₂ -, alkynyl-S(=O) ₂ -and haloalkyl-S(=O) ₂ -, haloalkenyl-S(=O) ₂ -and haloalkynyl-S(= O) ₂ -, where the terms "alkenyl", "alkynyl", "haloalkyl", "haloalkenyl" and "haloalkynyl" are as defined above.

The terms "alkylamino", "dialkylamino", "alkenylamino", "alkynylamino", "di(alkenyl)amino" and "di(alkynyl)amino" are Refers to the groups -NH (alkyl), -N (alkyl) ₂ , -NH (alkenyl), -NH (alkynyl), -N (alkenyl) ₂ and -N (alkynyl) ₂ , where the term "Alkyl", "alkenyl" and "alkynyl" are as defined above. In some embodiments, the alkyl component of the alkyl amine group or the dialkyl amine group will include C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ or C ₁ -C ₄ alkyl.

The terms "alkylcarbonyl", "alkoxycarbonyl", "alkylaminocarbonyl" and "dialkylaminocarbonyl" refer to alkyl-C(O)-, alkoxy-C(O)- , Alkylamino-C(O)- and dialkylamino-C(O)-, wherein alkyl, alkoxy, alkylamino and dialkylamino are as defined above. Similarly, the terms "haloalkylcarbonyl", "haloalkoxycarbonyl", "haloalkylaminocarbonyl" and "dihaloalkylaminocarbonyl" refer to the group haloalkyl-C(O)- , Haloalkoxy-C(O)-, haloalkylamino-C(O)- and dihaloalkylamino-C(O)-, among which haloalkyl, haloalkoxy, haloalkyl The amine group and the dihaloalkylamino group are as defined above.

Cross-reference of related applications This application claims the priority rights of U.S. Provisional Application No. 62/820,352 filed on March 19, 2019, which is incorporated herein by reference in its entirety.

其中： L為L1或L2：

； R¹ 為氫、氰基、鹵基、羥基、視情況經取代之烷基、視情況經取代之烷氧基、視情況經取代之烯基、視情況經取代之炔基、視情況經取代之芳基、視情況經取代之芳基氧基、視情況經取代之雜芳基、視情況經取代之環烷基、視情況經取代之環烷基氧基、視情況經取代之雜環基、視情況經取代之烷基羰基、視情況經取代之烷氧基羰基、胺基羰基、視情況經取代之烷基胺基羰基、視情況經取代之二烷基胺基羰基、-SO_p (視情況經取代之烷基或鹵烷基)、-SF₅ 或-NR^a R^b ，其中R^a 及R^b 獨立地為H或視情況經取代之烷基；或R^a 及R^b 可與其所連接之氮一起形成3員、4員、5員、6員、7員或8員雜環基，該雜環基可包括一至三個選自由N、O及S組成之群之額外雜原子且可視情況經取代； R² 為氫、視情況經取代之烷基、視情況經取代之環烷基或視情況經取代之芳基； R^2' 為視情況經取代之烷基、視情況經取代之環烷基或視情況經取代之芳基； R³ 為視情況經取代之烷基、視情況經取代之環烷基、視情況經取代之烷基羰基、視情況經取代之烷氧基羰基、胺基羰基、視情況經取代之烷基胺基羰基、視情況經取代之二烷基胺基羰基、-S(O)_p (視情況經取代之烷基)、-SF₅ 、視情況經取代之雜環基、視情況經取代之6員至10員芳基、視情況經取代之5員至10員雜芳基、螺環雜環基-碳環基、螺環雜環基-雜環基、螺環碳環基-碳環基、螺環碳環基-雜環基或-NR^a R^b ，其中R^a 及R^b 獨立地為H或視情況經取代之烷基；或R^a 及R^b 可與其所連接之氮一起形成3員、4員、5員、6員、7員或8員雜環基，該雜環基可包括一至三個選自由N、O及S組成之群之額外雜原子且可視情況經取代； R⁴ 在每次出現時獨立地為氫、氰基、氫、鹵基、羥基、視情況經取代之烷基、視情況經取代之烷氧基、視情況經取代之烯基、視情況經取代之炔基、視情況經取代之芳基、視情況經取代之芳基氧基、視情況經取代之雜芳基、視情況經取代之環烷基、視情況經取代之環烷基氧基、視情況經取代之雜環基、視情況經取代之烷基羰基、視情況經取代之烷氧基羰基、視情況經取代之胺基羰基、視情況經取代之烷基胺基羰基、視情況經取代之二烷基胺基羰基、-SO_p (視情況經取代之烷基或鹵烷基)、-SF₅ 或-NR^a R^b ，其中R^a 及R^b 獨立地為H或視情況經取代之烷基；或R^a 及R^b 可與其所連接之氮一起形成3員、4員、5員、6員、7員或8員雜環基，該雜環基可包括一至三個選自由N、O及S組成之群之額外雜原子且可視情況經取代； R⁵ 及R^5' 在每次出現時獨立地為氫、鹵素、氰基、硝基、羥基、視情況經取代之烷基、視情況經取代之烷氧基、視情況經取代之環烷基、視情況經取代之環烷基氧基、視情況經取代之芳基、視情況經取代之雜芳基、-SF₅ 、-SO_p (視情況經取代之烷基或鹵烷基)或-NR^c R^d ，其中R^c 及R^d 獨立地為H或視情況經取代之烷基；或R^c 及R^d 可與其所連接之氮一起形成3員、4員、5員、6員、7員或8員雜環基，該雜環基可包括一至三個選自由N、O及S組成之群之額外雜原子且可視情況經取代； R¹⁰ 為氫、鹵素、烷基、鹵烷基、環烷基、烯基或炔基； X為O或S； Q為O、S或N-R^2' ； Y¹ 、Y² 及Y³ 各自獨立地為N或-CR⁴ -； Y^1' 及Y^6' 各自獨立地為N、C或-CR⁵ -； Y^2' 、Y^3' 、Y^4' 及Y^5' 各自獨立地為N、NR² 、S、O、-CR⁵ -或CR⁵ R^5' ； W為CR⁶ R⁷ 、O、S或N-R⁸ ， Z為CR⁶ R⁷ 、O、S或N-R⁸ ， 其中 R⁶ 及R⁷ 在每次出現時獨立地為氫、鹵基、C₁ -C₄ 烷基、C₁ -C₄ 鹵烷基、C₁ -C₄ 烷氧基、C₁ -C₄ 鹵烷氧基或環烷氧基； R⁸ 為氫或C₁ -C₄ 烷基；且 其中Y^1' 、Y^2' 、Y^3' 、Y^4' 、Y^5' 及Y^6' 中之至多三者為雜原子； a為0或1； q為0或1； p在每次出現時獨立地為0、1或2；且 虛線鍵(

)表示單鍵或雙鍵； 或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽。An embodiment of the present invention includes a compound of formula (I):

Among them: L is L1 or L2:

; R ¹ is hydrogen, cyano, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted hetero Cyclic, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl,- SO _p (optionally substituted alkyl or haloalkyl of), - SF _5, or -NR ^a R ^b, wherein R ^a and R ^b are independently H or optionally substituted alkyl of; or R ^a and R ^b may form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group with the nitrogen to which it is attached, and the heterocyclic group may include one to three selected from the group consisting of N, O and S additional heteroatoms and optionally substituted; R ² is hydrogen, optionally substituted alkyl of, the optionally substituted cycloalkyl or optionally substituted aryl group of; R ^{2 'is} optionally substituted alkyl of , Optionally substituted cycloalkyl or optionally substituted aryl; R ³ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylcarbonyl, optionally substituted Substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -S(O) _p (optionally substituted alkyl), -SF ₅ , optionally substituted heterocyclic group, optionally substituted 6- to 10-membered aryl group, optionally substituted 5- to 10-membered heteroaryl group, spirocyclic heterocyclic group-carbocyclic group, spiro heterocyclyl - heterocyclyl, spiro carbocyclic group - carbocyclyl, carbocyclyl spiro - heterocyclic group or -NR ^a R ^b, wherein R ^a and R ^b are independently H or an optionally Substituted alkyl; or R ^a and R ^b together with the nitrogen to which they are attached can form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group, which may include one to three options Free additional heteroatoms of the group consisting of N, O and S and may be substituted as appropriate; R ⁴ is independently hydrogen, cyano, hydrogen, halo, hydroxyl, optionally substituted alkyl, optionally Optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl , Optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted heterocyclic group, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally Case substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO _p (optionally substituted alkyl or haloalkyl), -SF ₅ or -NR ^a R ^b, wherein R ^a and R ^b are independently H or optionally substituted alkyl of; or together with R ^a and R ^b may be the nitrogen to which they are attached A 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O and S and may be substituted as appropriate; R ⁵ and R ^{5 'at} each occurrence is independently hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted alkyl of, the optionally substituted alkoxy, optionally substituted cycloalkyl of Group, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted heteroaryl, -SF ₅ , -SO _p (optionally substituted alkyl or haloalkyl) Or -NR ^c R ^d , where R ^c and ^{Rd are} independently H or optionally substituted alkyl; or R ^c and ^Rd can form a 3-member, 4-member, 5-member or 6-member with the nitrogen to which they are attached A member, a 7-membered or an 8-membered heterocyclic group, the heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O and S and may be substituted as appropriate; R ¹⁰ is hydrogen, halogen, alkyl, Haloalkyl, cycloalkyl, alkenyl or alkynyl; X is O or S; Q is O, S or NR ^2' ; Y ¹ , Y ² and Y ³ are each independently N or -CR ⁴ -; Y ^{1 'and} Y ^6' are each independently N, C, or ^{-CR 5 -; Y 2 ',} Y 3', Y 4 ' and Y ^5' are each independently ^{N, NR 2, S, O} , -CR 5 -Or CR ⁵ R ^5' ; W is CR ⁶ R ⁷ , O, S or NR ⁸ , Z is CR ⁶ R ⁷ , O, S or NR ⁸ , where R ⁶ and R ⁷ are independently each time Hydrogen, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or cycloalkoxy; R ⁸ is hydrogen or C ₁ -C ₄ alkyl; and wherein ^{Y 1 ', Y 2',} Y 3 ', Y 4', up to three of the Y ^{5 'and} Y ^6' is a heteroatom; a is 0 or 1; q Is 0 or 1; p is independently 0, 1 or 2 each time it appears; and the dashed key (

) Represents a single bond or a double bond; or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof.

)如上文針對式(I)化合物所定義。In another embodiment, the present invention provides a compound of formula (I) wherein: R ¹ is hydrogen, cyano, halo, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy- C ₁ -C ₆ alkyl, hydroxy-C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkoxy-C ₁ -C ₆ alkyl, amino-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ halo alkenyl , C ₂ -C ₆ alkynyl, C ₂ -C ₆ haloalkynyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C _1- C ₆ haloalkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ haloalkylaminocarbonyl, di-C ₁ -C ₆ alkylaminocarbonyl, di- C ₁ -C ₆ haloalkylaminocarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted C ₃ -C ₈ ring Alkyl group, optionally substituted C ₃ -C ₈ cycloalkyloxy group, optionally substituted 3- to 7-membered heterocyclic group, -SF ₅ , -SO _p (optionally substituted C ₁ -C _alkyl or halo C ₁ -C ₆ alkyl), or -NR ^a R ^b, wherein R ^a and R ^b are independently H or optionally substituted alkyl of C ₁ -C _6; or R ^a and R ^b It can form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group with the nitrogen to which it is attached, and the heterocyclic group may include one to three additional members selected from the group consisting of N, O and S Heteroatom and optionally substituted; R ² is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted benzene R ^2'is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted phenyl; R ³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkoxy-C ₁ -C ₆ alkyl, Optionally substituted C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkane Oxycarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ haloalkylaminocarbonyl, di-C ₁ -C ₆ alkylaminocarbonyl, di-C ₁ -C ₆ haloalkylaminocarbonyl, -SF ₅ , -S(O) _p (C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl), containing one to three selected from N, O and The heteroatoms of the group consisting of S are optionally substituted 3-membered to 7-membered heterocyclic groups, optionally substituted phenyl groups, optionally substituted 5-membered to 10-membered heteroaryl groups, 5-membered to 11-membered spiro groups Cyclic heterocyclyl-carbocyclyl, 5-membered to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5-membered to 11-membered spirocyclic carbocyclyl-carbocyclyl, 5-membered to 11-membered spirocyclic carbocyclyl- heterocyclyl or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or R ^a and R ^b may be the nitrogen to which they are attached Together to form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group, the heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O and S, and may be subject to Substitution; ^{each occurrence of R 4} is independently hydrogen, cyano, halo, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ haloalkynyl, C ₁ -C ₆ alkoxy -C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkoxy C ₁ -C ₆ alkyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted 5 members Or 6-membered heteroaryl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkyloxy, containing one to three selected from N, O and S Group of heteroatoms optionally substituted 3- to 7-membered heterocyclic group, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ haloalkylaminocarbonyl, di-C ₁ -C ₆ alkylaminocarbonyl, two -C ₁ -C ₆ haloalkylaminocarbonyl, -SO _p (optionally substituted C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl), SF ₅ or -NR ^a R ^b , wherein R ^a and R ^{b are} independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or R ^a and R ^b may form a 3-member, 4-member, 5-member, and the nitrogen to which they are attached. A 6-membered, 7-membered or 8-membered heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O and S and may be substituted as appropriate; R ⁵ and R ^5' When it appears, it is independently hydrogen, halogen, cyano, nitro, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkane Oxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkoxy-C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₈ cycloalkane Group, optionally substituted C ₃ -C ₈ cycloalkyloxy, optionally substituted benzene Group, optionally substituted 5-membered or 6-membered heteroaryl, -SF ₅ , -SO _p (optionally substituted C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl) or -NR ^c R ^d , where R ^c and R ^{d are} independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or R ^c and R ^d can form a 3-member or 4-member with the nitrogen to which they are attached , 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group, the heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O and S and may be substituted as appropriate; R ¹⁰ is hydrogen, Halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; and L, X, Q , Y ¹ , Y ² , Y ³ , Y ^1' , Y ^2' , Y ^3' , Y ^4' , Y ^5' , Y ^6' , W, Z, R ⁶ , R ⁷ , R ⁸ , a, q , P and dashed key (

) Is as defined above for the compound of formula (I).

In one embodiment, L is L1. In another embodiment, L is L2. In some embodiments: R ¹ is hydrogen, cyano, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, optionally substituted C ₁ -C ₄ alkenyl, optionally substituted C ₁ -C ₄ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted saturated or unsaturated 5-membered, 6-membered or 7-membered heterocycle Group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted C ₁ -C ₄ alkylcarbonyl, optionally substituted C ₁ -C ₄ alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C ₁ -C ₄ alkylaminocarbonyl, optionally substituted C ₁ -C ₄ dialkylaminocarbonyl, Optionally substituted alkyl -SO _p -, haloalkyl -SO _p -, amine group, -NH- optionally substituted C ₁ -C ₄ alkyl or -NR ^a R ^b , wherein R ^a and R ^{b is} independently optionally substituted alkyl; or R ^a and R ^b may form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group together with the nitrogen to which they are attached, the heterocyclic ring The group may include one to three additional heteroatoms selected from the group consisting of N, O and S and may be substituted as appropriate; R ² is hydrogen or C ₁ -C ₄ alkyl; R ³ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, 4-membered to 6-membered heterocyclic group, 6-membered to 10-membered aryl group, 5-membered to 10-membered heteroaryl group, each of which may be substituted with 1, 2, or 3 as appropriate Group substitution; each R ^{4 is} independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, optionally Cases substituted C ₃ -C ₈ cycloalkyl, -amino, NH-optionally substituted C ₁ -C ₄ alkyl, -SF ₅ or -NR ^a R ^b , wherein R ^c and R ^{d are} independently It is optionally substituted C ₁ -C ₄ alkyl; or R ^a and R ^b can form optionally substituted 3, 4, 5, 6, 7 or 8 members together with the nitrogen to which they are attached Heterocyclic group, SO _p (optionally substituted C ₁ -C ₄ alkyl or haloalkyl); each R ^{5 is} independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted C _1- C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, optionally substituted C ₃ -C ₈ cycloalkyl, -amino, NH- optionally substituted C ₁ -C ₄ alkyl, -SF ₅ or -NR ^c R ^d , where R ^c and ^{Rd are} independently optionally substituted C ₁ -C ₄ alkyl; or R ^c and ^Rd can be formed together with the nitrogen to which they are attached Optionally substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group, SO _p (optionally substituted C ₁ -C ₄ alkyl or haloalkyl).

In some embodiments, R ¹ is hydrogen.

In some embodiments, R ¹ is C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, amino, C ₁ -C ₄ alkylamino, or di-(C ₁ -C ₄ alkyl) Amine group.

In another embodiment, R ¹ is halogen.

In another embodiment, R ¹ is C ₁ -C ₄ alkyl -SO _p -, C ₁ -C ₄ haloalkyl -SO _p -or -SF ₅ .

In other embodiments, R ¹ is hydroxy-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkoxy-C ₁ -C ₄ haloalkyl.

In another embodiment, R ¹ is methyl, ethyl, propyl, butyl, pentyl, isopropyl ( i- Pr), tert-butyl/ t -butyl, propyl- 1-en-2-yl, 2-fluoroprop-2-yl or 2-hydroxyprop-2-yl.

In another embodiment, R ¹ is CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ or -CF ₂ CF ₃ .

In some embodiments, R ¹ is C ₂ -C ₄ alkenyl or C ₂ -C ₄ haloalkenyl.

In some embodiments, R ¹ is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

In some embodiments, R ¹ is optionally substituted saturated or unsaturated 6-membered heterocyclyl.

In one embodiment embodiment, R ¹ is -NR ^a R ^b, wherein R ^a and R ^b are independently hydrogen or C ₁ -C ₆ alkyl. In another embodiment, R ¹ is -NR ^a R ^b, wherein R ^a and R ^b may be taken together with the nitrogen to which they are attached 3, 4, 5, 6, 7 or 8-membered heterocyclic group , The heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may be substituted as appropriate.

In another embodiment, R ¹ is C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxycarbonyl, Aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ haloalkylaminocarbonyl, di-C ₁ -C ₆ alkylaminocarbonyl, di-C ₁ -C ₆ haloalkyl Aminocarbonyl.

In some embodiments, R ¹ is optionally substituted tetrahydrofuranyl, dihydrofuranyl, N-morpholinyl, piperanyl, dihydropiperanyl, piperidinyl, dihydropiperidinyl, dihydro Thiophene or tetrahydrothiophene.

In some embodiments, R ¹ is optionally substituted phenyl.

In some embodiments, R ¹ is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl , Imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazoline, isoxazolyl, thiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, isothiazole Ridinyl, furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-side oxypiperazinyl, 2-side oxypiperidinyl, 2-side oxypyrrolidine Group, 2-side oxyazinyl, azinyl, 4-piperidone, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperanyl, dihydropiperanyl, tetrahydropiperan Group, thiopiperanyl, dihydrothiopiperanyl, tetrahydrothiopiperanyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfonium, thiamorpholinyl sulfonium, 1,3- Dioxolane and tetrahydro-1,1-di-side oxythienyl, triazolyl or triazinyl.

In some embodiments, R ¹ is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, or morpholinyl, all of which are optionally substituted with one or more halogens .

In some embodiments, R ³ is a 6- to 10-membered aryl group substituted with 1, 2, 3, 4, or 5 substituents as appropriate.

In some embodiments, R ³ is C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl.

In some embodiments, R ³ is methyl, ethyl, n-propyl, n-butyl, isopropyl, tertiary butyl, second butyl, or isobutyl.

In other embodiments, R ³ is CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ or -CF ₂ CF ₃ .

In some embodiments, R ³ is optionally substituted C ₃ -C ₈ cycloalkyl. In still other embodiments, R ³ is optionally substituted C ₃ -C ₆ cycloalkyl. In still other embodiments, R ³ is optionally substituted C ₃ -C ₈ cycloalkenyl or C ₃ -C ₆ cycloalkenyl. In some embodiments, R ³ is optionally substituted cyclopentyl or cyclohexyl.

In one embodiment, R ³ is a cyclohexyl group substituted with one or more halo groups, C ₁ -C ₃ alkyl groups, or C ₁ -C ₃ haloalkyl groups as appropriate. In another embodiment, R ³ is cyclohexyl substituted with 1 or 2 fluorine, chlorine or CF _3.

In some embodiments, R ³ is optionally substituted piperidinyl, morpholinyl, tetrahydrofuranyl, or dihydrofuranyl. In some embodiments, R ³ is piperidinyl, morpholinyl, tetrahydrofuranyl, or dihydrofuranyl substituted with one or more halo, C ₁ -C ₆ alkyl, or C ₁ -C _{6 haloalkyl} . In another embodiment, R ³ is piperidinyl, morpholinyl, tetrahydrofuranyl or dihydrofuranyl substituted with one or more methyl, chlorine or fluorine.

In some embodiments, R ³ is a 5- to 10-membered heteroaryl group substituted with 1, 2, 3, 4, or 5 substituents as appropriate. In one embodiment, the 5-membered to 10-membered heteroaryl group is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolyl, isoquinolyl, quinolyl Azolinyl, quinolinyl, furanyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuran Group, benzothienyl, imidazopyridyl, imidazopyrimidinyl or pyrrolopyrimidinyl.

In other embodiments, R ³ is optionally substituted spirocyclic heterocyclyl-carbocyclyl, optionally substituted spirocyclic heterocyclyl-heterocyclyl, optionally substituted spirocyclic carbocyclyl- Carbocyclyl or optionally substituted spirocyclic carbocyclyl-heterocyclic group. In other embodiments, R ³ is 5 to 11 members optionally substituted spirocyclic heterocyclyl-carbocyclyl, 5 to 11 members optionally substituted spirocyclic heterocyclyl-heterocyclyl, 5 A spiro carbocyclyl-carbocyclyl group with 5 to 11 members optionally substituted or a spiro carbocyclyl-heterocyclic group with 5 to 11 members optionally substituted. Non-limiting examples of spirocyclic carbocyclyl-carbocyclyl, spirocyclic carbocyclyl-heterocyclyl and spirocyclic heterocyclyl-heterocyclyl are shown below for illustration.

However, it will be obvious to those familiar with the art that the second ring of the spiro group can be attached to any available carbon in the first ring. It will also be understood that the first ring of the spirocyclic group can be bonded to the molecule at any available atom. Therefore, the present invention includes 3-membered, 4-membered, 5-membered, 6-membered and 7-membered carbocyclic or heterocyclic ring as defined herein, which is connected to the second 3-membered or 4-membered at any available carbon atom in the first ring , 5-member, 6-member and 7-member carbocyclic or heterocyclic ring.

In some embodiments, R ³ is phenyl substituted with 1 to 4 substituents. In another embodiment, R ³ is phenyl substituted with 1 to 3 substituents. In another embodiment, R ³ is phenyl substituted with 1 or 2 substituents. In some embodiments, R ³ is phenyl substituted with 1, 2, 3, or 4 substituents, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, haloalkyl Sulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, substituted phenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkene Group, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy or haloalkenoxy.

In some embodiments, R ³ is a para-substituted phenyl group.

In some embodiments, R ³ is a meta-substituted phenyl group.

In some embodiments, R ³ is phenyl substituted by the ortho position.

In some embodiments, R ³ is halophenyl. In some embodiments, R ³ is haloalkylphenyl.

In some embodiments, R ³ is haloalkoxyphenyl.

In some embodiments, R ³ is a phenyl group substituted with 2 substituents, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl , Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, halo Alkoxy or haloalkenyloxy.

In some embodiments, R ³ is 2,3-disubstituted phenyl.

In some embodiments, R ³ is 2,4-disubstituted phenyl.

In some embodiments, R ³ is 2,5-disubstituted phenyl.

In some embodiments, R ³ is 2-,6-disubstituted phenyl.

In some embodiments, R ³ is 3-,5-disubstituted phenyl.

In other embodiments, R ³ is 3-,4-disubstituted phenyl.

In other embodiments, R ³ is 3-,6-disubstituted phenyl.

In some embodiments, R ³ is dihalophenyl, such as dichloro; difluoro; or chlorine, fluorine.

In some embodiments, R ³ is 2,3-dihalophenyl.

In some embodiments, R ³ is chlorophenyl. In another embodiment, R ³ is fluorophenyl. In another embodiment, R ³ is dichlorophenyl. In another embodiment, R ³ is difluorophenyl. In another embodiment, R ³ is 3,5-dichlorophenyl. In another embodiment, R ³ is 3,5-difluorophenyl. In another embodiment, R ³ is 2,6-dichlorophenyl. In another embodiment, R ³ is 2,6-difluorophenyl.

In some embodiments, R ³ is phenyl substituted with halo and haloalkyl.

In some embodiments, R ³ is phenyl substituted with halo and haloalkoxy.

In some embodiments, R ³ is phenyl substituted with haloalkyl and haloalkoxy.

In some embodiments, R ³ is phenyl substituted with 3 substituents, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, alkyl , Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, halo Alkoxy or haloalkenyloxy.

In some embodiments, R ³ is a trihalophenyl group, such as trichloro; trifluoro; or chlorine, chlorine, fluorine; or fluorine, fluorine, or chlorine.

In some embodiments, R ³ is phenyl substituted with 2 halo and haloalkyl.

In some embodiments, R ³ is phenyl substituted with 2 halo and haloalkoxy.

In some embodiments, R ³ is phenyl substituted with 1 haloalkyl, 1 halo, and 1 haloalkoxy.

In some embodiments, R ³ is phenyl substituted with 1 halo group and 2 haloalkyl groups.

In some embodiments, R ³ is a 5-membered heteroaryl group optionally substituted with 1 or 2 substituents, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, haloalkane Sulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy Group, alkynyloxy, haloalkoxy or haloalkenoxy.

In some embodiments, R ³ is a 6-membered heteroaryl group optionally substituted with 1 or 2 substituents, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, haloalkane Sulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy Group, alkynyloxy, haloalkoxy or haloalkenoxy.

In some embodiments, R ³ is 2-pyridyl substituted with 1 or 2 substituents as appropriate, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, haloalkyl Sulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy , Alkynyloxy, haloalkoxy or haloalkenyloxy.

In some embodiments, R ³ is 3-pyridyl substituted with 1 or 2 substituents as appropriate, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, haloalkyl Sulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy , Alkynyloxy, haloalkoxy or haloalkenyloxy.

In some embodiments, R ³ is 4-pyridyl substituted with 1 or 2 substituents as appropriate, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, haloalkyl Sulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy , Alkynyloxy, haloalkoxy or haloalkenyloxy.

In another embodiment, R ³ is 4-pyridyl which is unsubstituted or substituted with 1 or 2 chlorine or fluorine. In yet another embodiment, R ³ is 3-pyridyl that is unsubstituted or substituted with 1 or 2 chlorine or fluorine.

In other embodiments, R ³ is an optionally substituted 3- to 7-membered heterocyclic ring. In some embodiments, R ³ is optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl , Pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazoline, isoxazolyl, thiazolyl, thiadiazolyl, thiazolyl, iso Thiazolyl, isothiazolidinyl, furyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-side oxypiperazinyl, 2-side oxypiperidinyl, 2- Pendant oxypyrrolidinyl, 2-side oxyazinyl, azinyl, 4-piperidinone, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropiperanyl, morpholinyl , Thimorpholinyl, Thimorpholinyl sulfide, Thimorpholinyl sulfide, 1,3-dioxolane and tetrahydro-1,1-di-side oxythiophene, triazolyl or triazine base.

In another embodiment, R ³ can be a heterocyclic ring bridging bicyclic group optionally substituted.

In some embodiments, each R ^{4 is} independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, amino, C ₁ -C ₄ alkylamino, or di-(C _1- C ₄ alkyl) amine group.

In another embodiment, each R ^{4 is} independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, second butyl, isobutyl, or tertiary butyl.

In another embodiment, each R ^{4 is} independently hydrogen, CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ or -CF ₂ CF ₃ .

In some embodiments, R ⁴ is hydrogen.

In some embodiments, R ⁴ is halogen.

In another embodiment, R ⁴ is fluorine or chlorine.

In another embodiment, each R ^{4 is} independently hydrogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, or S(O) _p (C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl), wherein p is 0, 1, or 2.

In another embodiment, R ₄ is methoxy, ethoxy, propoxy or butoxy.

In another embodiment, R ₄ is methylthio, ethylthio, propylthio, or butylthio.

In another embodiment, R ₄ is -OCF ₃ or -SCF ₃ .

In some embodiments, R ⁴ is C ₁ -C ₄ alkenyl or C ₁ -C ₄ haloalkenyl.

In some embodiments, R ⁴ is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

In some embodiments, R ⁴ is optionally substituted saturated or unsaturated 6-membered heterocyclyl.

In some embodiments, R ⁴ is optionally substituted tetrahydrofuranyl, dihydrofuranyl, N-morpholinyl, piperanyl, dihydropiperanyl, piperidinyl, dihydropiperidinyl, dihydro Thiophene or tetrahydrothiophene.

In some embodiments, R ⁴ is optionally substituted phenyl.

In other embodiments, R ⁴ is phenyl substituted with 1, 2 or 3 substituents, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl Group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, Alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy.

In another embodiment, R ⁴ is a 5-membered or 6-membered heteroaryl group with 1 or 2 substituents, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, halo Alkylsulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyl Oxy, alkynyl, haloalkoxy or haloalkenyloxy.

In some embodiments, R ⁴ is optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl , Pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazoline, isoxazolyl, thiazolyl, thiadiazolyl, thiazolyl, iso Thiazolyl, isothiazolidinyl, furyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-side oxypiperazinyl, 2-side oxypiperidinyl, 2- Pendant oxypyrrolidinyl, 2-side oxyazinyl, azinyl, 4-piperidinone, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropiperanyl, morpholinyl , Thimorpholinyl, Thimorpholinyl sulfide, Thimorpholinyl sulfide, 1,3-dioxolane and tetrahydro-1,1-di-side oxythiophene, triazolyl or triazine base.

In some embodiments, R ⁴ is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, or morpholinyl, all of which are optionally substituted with one or more halogens .

In some embodiments, R ⁵ is hydrogen.

In some embodiments, each R ^{5 is} independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, amino, C ₁ -C ₄ alkylamino, or di-(C _1- C ₄ alkyl) amine group.

In another embodiment, each R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, second butyl, isobutyl, or tertiary butyl.

In another embodiment, R ⁵ is CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ or -CF ₂ CF ₃ .

In some embodiments, R ⁵ is halogen.

In another embodiment, R ⁵ is fluorine or chlorine.

In another embodiment, R ⁵ is C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or S(O) _p (C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl基), where p is 0, 1, or 2.

In another embodiment, R ₅ is methoxy, ethoxy, propoxy or butoxy.

In another embodiment, R ₅ is methylthio, ethylthio, propylthio, or butylthio.

In another embodiment, R ₅ is -OCF ₃ or -SCF ₃ .

In some embodiments, R ⁵ is C ₁ -C ₄ alkenyl or C ₁ -C ₄ haloalkenyl.

In some embodiments, R ⁵ is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

In some embodiments, R ⁵ is optionally substituted tetrahydrofuranyl, dihydrofuranyl, N-morpholinyl, piperanyl, dihydropiperanyl, piperidinyl, dihydropiperidinyl, dihydro Thiophene or tetrahydrothiophene.

In some embodiments, R ⁵ is optionally substituted phenyl.

In other embodiments, R ⁵ is phenyl substituted with 1, 2 or 3 substituents, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl Group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, Alkenyloxy, alkynyloxy, haloalkoxy or haloalkenyloxy.

In other embodiments, R ⁵ is a 5-membered or 6-membered heteroaryl group with 1 or 2 substituents, and these substituents are independently halo, cyano, nitro, alkylsulfonyl, haloalkane Sulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenoxy Group, alkynyloxy, haloalkoxy or haloalkenoxy.

In some embodiments, R ⁵ is optionally substituted aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl , Pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazoline, isoxazolyl, thiazolyl, thiadiazolyl, thiazolyl, iso Thiazolyl, isothiazolidinyl, furyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-side oxypiperazinyl, 2-side oxypiperidinyl, 2- Pendant oxypyrrolidinyl, 2-side oxyazinyl, azinyl, 4-piperidinone, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropiperanyl, morpholinyl , Thimorpholinyl, Thimorpholinyl sulfide, Thimorpholinyl sulfide, 1,3-dioxolane and tetrahydro-1,1-di-side oxythiophene, triazolyl or triazine base.

In some embodiments, R ⁵ is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, or morpholinyl, all of which are optionally substituted with one or more halogens .

In some embodiments, a is zero.

In some embodiments, a is 1.

In some embodiments, X is O.

In some embodiments, X is S.

In some embodiments, Q is O.

In some embodiments, Q is S.

In some embodiments, Q is NR ^2' .

In some embodiments, W is CH ₂ .

In some embodiments, Z is CH ₂ .

In some embodiments, Z is O.

In some embodiments, Z is S.

In some embodiments, Z is NH.

其中變數L、R¹ 、R³ 、Y¹ 、Y² 、Y³ 、Y^1' 、Y^3' 、Y^4' 、Y^5' 、Y^6' 、X、W、Z、R¹⁰ 及a如針對式(I)所定義。In some embodiments, the compound of formula (I) is a compound of formula (I-1):

Among them, the variables L, R ¹ , R ³ , Y ¹ , Y ² , Y ³ , Y ^1' , Y ^3' , Y ^4' , Y ^5' , Y ^6' , X, W, Z, R ¹⁰ and a such as Defined for formula (I).

其中變數R¹ 、R² 、R³ 、Y¹ 、Y² 、Y³ 、Y^2' 、Y^3' 、Y^4' 、Y^5' 、X、Q、W、Z、R¹⁰ 及a如針對式(I)所定義。In some embodiments, the compound of formula (I) is a compound of formula (I-2):

Among them, the variables R ¹ , R ² , R ³ , Y ¹ , Y ² , Y ³ , Y ^2' , Y ^3' , Y ^4' , Y ^5' , X, Q, W, Z, R ¹⁰ and a are for Defined by formula (I).

其中變數R¹ 、R² 、R³ 、Y¹ 、Y² 、Y³ 、Y^2' 、Y^3' 、Y^4' 、Y^5' 、X、Q、W、Z、R¹⁰ 及a如針對式(I)所定義。In other embodiments, the compound of formula (I) is the compound of formula (I-3) as follows:

Among them, the variables R ¹ , R ² , R ³ , Y ¹ , Y ² , Y ³ , Y ^2' , Y ^3' , Y ^4' , Y ^5' , X, Q, W, Z, R ¹⁰ and a are for Defined by formula (I).

其中變數R¹ 、R² 、R³ 、Y¹ 、Y² 、Y³ 、Y^1' 、Y^3' 、Y^4' 、Y^5' 、Y^6' 、X、Q、W、Z、R¹⁰ 及a如針對式(I)所定義。In other embodiments, the compound of formula (I) is a compound of formula (I-4):

The variables R ¹ , R ² , R ³ , Y ¹ , Y ² , Y ³ , Y ^1' , Y ^3' , Y ^4' , Y ^5' , Y ^6' , X, Q, W, Z, R ¹⁰ And a are as defined for formula (I).

其中變數R¹ 、R² 、R³ 、Y¹ 、Y² 、Y³ 、Y^1' 、Y^3' 、Y^4' 、Y^5' 、Y^6' 、X、Q、W、Z、R¹⁰ 及a如針對式(I)所定義。In another embodiment, the compound of formula (I) is a compound of formula (I-5):

The variables R ¹ , R ² , R ³ , Y ¹ , Y ² , Y ³ , Y ^1' , Y ^3' , Y ^4' , Y ^5' , Y ^6' , X, Q, W, Z, R ¹⁰ And a are as defined for formula (I).

其中變數Y¹ 、Y² 、Y³ 、R¹ 、R² 、R³ 、W、Z、Y^2' 、Y^3' 、Y^4' 、Y^5' 、R¹⁰ 及a如針對式(I)所定義。In some embodiments, the compound of formula (I) is a compound of formula (Ia):

The variables Y ¹ , Y ² , Y ³ , R ¹ , R ² , R ³ , W, Z, Y ^2' , Y ^3' , Y ^4' , Y ^5' , R ¹⁰ and a are as for formula (I) Defined.

其中變數Y¹ 、Y² 、Y³ 、R¹ 、R² 、R³ 、R⁵ 、W、Z、R¹⁰ 及a如針對式(I)所定義，且o為0、1、2、3或4。In some embodiments, the compound of formula (I) is a compound of formula (Ib):

The variables Y ¹ , Y ² , Y ³ , R ¹ , R ² , R ³ , R ⁵ , W, Z, R ¹⁰ and a are as defined for formula (I), and o is 0, 1, 2, 3 Or 4.

其中變數R¹ 、R² 、R³ 、R⁴ 、R⁵ 、W、Z、R¹⁰ 及a如針對式(I)所定義；n為0、1或2；且o為0、1、2、3或4。In some embodiments, the compound of formula (I) is a compound of formula (Ic):

Wherein the variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, Z, R ¹⁰ and a are as defined for formula (I); n is 0, 1 or 2; and o is 0, 1, 2 , 3, or 4.

其中變數R¹ 、R² 、R³ 、R⁴ 、R⁵ 、W、Z、R¹⁰ 及a如針對式(I)所定義；n為0、1或2；且o為0、1、2、3或4。In other embodiments, the compound of formula (I) is a compound of formula (Id):

Wherein the variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, Z, R ¹⁰ and a are as defined for formula (I); n is 0, 1 or 2; and o is 0, 1, 2 , 3, or 4.

其中變數R¹ 、R² 、R³ 、R⁴ 、R⁵ 、W、Z、R¹⁰ 及a如針對式(I)所定義；且o為0、1、2、3或4。In some embodiments, the compound of formula (I) is a compound of formula (Ie):

The variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, Z, R ¹⁰ and a are as defined for formula (I); and o is 0, 1, 2, 3 or 4.

其中變數R¹ 、R² 、R³ 、R⁴ 、R⁵ 、W、Z、R¹⁰ 及a如針對式(I)所定義；且o為0、1、2、3或4。In some embodiments, the compound of formula (I) is a compound of formula (If):

The variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, Z, R ¹⁰ and a are as defined for formula (I); and o is 0, 1, 2, 3 or 4.

其中變數R¹ 、R² 、R³ 、R⁴ 、R⁵ 、W、Z、R¹⁰ 及a如針對式(I)所定義；n為0、1或2；且o為0、1、2、3或4。In some embodiments, the compound of formula (I) is a compound of formula (Ig):

Wherein the variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, Z, R ¹⁰ and a are as defined for formula (I); n is 0, 1 or 2; and o is 0, 1, 2 , 3, or 4.

其中變數R¹ 、R² 、R³ 、R⁴ 、R⁵ 、W、Z、R¹⁰ 及a如針對式(I)所定義；且o為0、1、2、3或4。In other embodiments, the compound of formula (I) is a compound of formula (Ih):

The variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, Z, R ¹⁰ and a are as defined for formula (I); and o is 0, 1, 2, 3 or 4.

其中變數R¹ 、R² 、R³ 、R⁴ 、R⁵ 、W、Z、R¹⁰ 及a如針對式(I)所定義；n為0、1、2或3；且o為0、1、2、3或4。In some embodiments, the compound of formula (I) is a compound of formula (Ii):

Wherein the variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, Z, R ¹⁰ and a are as defined for formula (I); n is 0, 1, 2 or 3; and o is 0, 1. , 2, 3, or 4.

Those familiar with the art will understand that in any of formula (Ib) to formula (Ii), when the indicator variables R ⁴ and R ^{5 are} in the form of substituents on the aromatic ring (for example, as (R ⁴ ) _n and (R ⁵ ) _o group form, where n is 0, 1, 2 or 3 and o is 0, 1, 2, 3 or 4) when they are present, these variables will represent non-hydrogen substituents, this is due to In an embodiment where n and o are 0, R ⁴ and R ⁵ will not be present.

In other embodiments, the present invention includes compounds of formula (I), which have the structures of formula (Ia) to formula (Ii) shown above but in which the sulfur atom corresponding to the variable X in formula (I) is passed through oxygen Atom replacement. Therefore, the present invention provides formulas (Ia'), (Ib'), (Ic'), (Id'), (Ie'), (If'), (Ig'), (Ih') and (Ii') Compounds, which correspond to formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) and (Ii) but wherein formula (Ia) to formula ( The sulfur atom in Ii) corresponding to the variable X in formula (I) is replaced by oxygen.

表1 式 Y¹ Y² Y³ Y^2' Y^3' Y^4' Y^5' IA-1 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ IA-2 CR⁴ CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ IA-3 CR⁴ CR⁴ CR⁴ CR⁵ N CR⁵ CR⁵ IA-4 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ N CR⁵ IA-5 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ N IA-6 CR⁴ CR⁴ CR⁴ N N CR⁵ CR⁵ IA-7 CR⁴ CR⁴ CR⁴ CR⁵ N N CR⁵ IA-8 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ N N IA-9 N CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ IA-10 N CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ IA-11 N CR⁴ CR⁴ CR⁵ N CR⁵ CR⁵ IA-12 N CR⁴ CR⁴ CR⁵ CR⁵ N CR⁵ IA-13 N CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ N IA-14 N CR⁴ CR⁴ N N CR⁵ CR⁵ IA-15 N CR⁴ CR⁴ CR⁵ N N CR⁵ IA-16 N CR⁴ CR⁴ CR⁵ CR⁵ N N IA-17 CR⁴ N CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ IA-18 CR⁴ N CR⁴ N CR⁵ CR⁵ CR⁵ IA-19 CR⁴ N CR⁴ CR⁵ N CR⁵ CR⁵ 1A-20 CR⁴ N CR⁴ CR⁵ CR⁵ N CR⁵ IA-21 CR⁴ N CR⁴ CR⁵ CR⁵ CR⁵ N IA-22 CR⁴ N CR⁴ N N CR⁵ CR⁵ IA-23 CR⁴ N CR⁴ CR⁵ N N CR⁵ IA-24 CR⁴ N CR⁴ CR⁵ CR⁵ N N IA-25 CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ CR⁵ IA-26 CR⁴ CR⁴ N N CR⁵ CR⁵ CR⁵ IA-27 CR⁴ CR⁴ N CR⁵ N CR⁵ CR⁵ IA-28 CR⁴ CR⁴ N CR⁵ CH N CR⁵ IA-29 CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ N IA-30 CR⁴ CR⁴ N N N CR⁵ CR⁵ IA-31 CR⁴ CR⁴ N CR⁵ N N CR⁵ IA-32 CR⁴ CR⁴ N CR⁵ CR⁵ N N IA-33 N N CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ IA-34 N N CR⁴ N CR⁵ CR⁵ CR⁵ IA-35 N N CR⁴ CR⁵ N CR⁵ CR⁵ IA-36 N N CR⁴ CR⁵ CR⁵ N CR⁵ IA-37 N N CR⁴ CR⁵ CR⁵ CR⁵ N IA-38 N N CR⁴ N N CR⁵ CR⁵ IA-39 N N CR⁴ CR⁴ N N CR⁵ IA-40 N N CR⁴ CR⁵ CR⁵ N N IA-41 CR⁴ N N CR⁵ CR⁵ CR⁵ CR⁵ IA-42 CR⁴ N N N CR⁵ CR⁵ CR⁵ IA-43 CR⁴ N N CR⁵ N CR⁵ CR⁵ IA-44 CR⁴ N N CR⁵ CR⁵ N CR⁵ IA-45 CR⁴ N N CR⁵ CR⁵ CR⁵ N IA-46 CR⁴ N N N N CR⁵ CR⁵ IA-47 CR⁴ N N CR⁵ N N CR⁵ IA-48 CR⁴ N N CR⁵ CR⁵ N N IA-49 N CR⁴ N CR⁵ CR⁵ CR⁵ CR⁵ IA-50 N CR⁴ N N CR⁵ CR⁵ CR⁵ IA-51 N CR⁴ N CR⁵ N CR⁵ CR⁵ IA-52 N CR⁴ N CR⁵ CR⁵ N CR⁵ IA-53 N CR⁴ N CR⁵ CR⁵ CR⁵ N IA-54 N CR⁴ N N N CR⁵ CR⁵ IA-55 N CR⁴ N CR⁵ N N CR⁵ IA-56 N CR⁴ N CR⁵ CR⁵ N N In other embodiments, the present invention provides a compound of formula (IA), wherein the variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, W, Z, R ¹⁰ and a are as described above for formula (I) defined above, and ^{Y 1, Y 2, Y 3} , Y 2 ', Y 3', Y 4 ' and Y ^5' as shown in table 1:

Table 1 formula Y ¹ Y ² Y ³ Y ^2' Y ^3' Y ^4' Y ^5' IA-1 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ IA-2 CR ⁴ CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ IA-3 CR ⁴ CR ⁴ CR ⁴ CR ⁵ N CR ⁵ CR ⁵ IA-4 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ N CR ⁵ IA-5 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ N IA-6 CR ⁴ CR ⁴ CR ⁴ N N CR ⁵ CR ⁵ IA-7 CR ⁴ CR ⁴ CR ⁴ CR ⁵ N N CR ⁵ IA-8 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ N N IA-9 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ IA-10 N CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ IA-11 N CR ⁴ CR ⁴ CR ⁵ N CR ⁵ CR ⁵ IA-12 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ N CR ⁵ IA-13 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ N IA-14 N CR ⁴ CR ⁴ N N CR ⁵ CR ⁵ IA-15 N CR ⁴ CR ⁴ CR ⁵ N N CR ⁵ IA-16 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ N N IA-17 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ IA-18 CR ⁴ N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ IA-19 CR ⁴ N CR ⁴ CR ⁵ N CR ⁵ CR ⁵ 1A-20 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ N CR ⁵ IA-21 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ CR ⁵ N IA-22 CR ⁴ N CR ⁴ N N CR ⁵ CR ⁵ IA-23 CR ⁴ N CR ⁴ CR ⁵ N N CR ⁵ IA-24 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ N N IA-25 CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ CR ⁵ IA-26 CR ⁴ CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ IA-27 CR ⁴ CR ⁴ N CR ⁵ N CR ⁵ CR ⁵ IA-28 CR ⁴ CR ⁴ N CR ⁵ CH N CR ⁵ IA-29 CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ N IA-30 CR ⁴ CR ⁴ N N N CR ⁵ CR ⁵ IA-31 CR ⁴ CR ⁴ N CR ⁵ N N CR ⁵ IA-32 CR ⁴ CR ⁴ N CR ⁵ CR ⁵ N N IA-33 N N CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ IA-34 N N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ IA-35 N N CR ⁴ CR ⁵ N CR ⁵ CR ⁵ IA-36 N N CR ⁴ CR ⁵ CR ⁵ N CR ⁵ IA-37 N N CR ⁴ CR ⁵ CR ⁵ CR ⁵ N IA-38 N N CR ⁴ N N CR ⁵ CR ⁵ IA-39 N N CR ⁴ CR ⁴ N N CR ⁵ IA-40 N N CR ⁴ CR ⁵ CR ⁵ N N IA-41 CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ CR ⁵ IA-42 CR ⁴ N N N CR ⁵ CR ⁵ CR ⁵ IA-43 CR ⁴ N N CR ⁵ N CR ⁵ CR ⁵ IA-44 CR ⁴ N N CR ⁵ CR ⁵ N CR ⁵ IA-45 CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ N IA-46 CR ⁴ N N N N CR ⁵ CR ⁵ IA-47 CR ⁴ N N CR ⁵ N N CR ⁵ IA-48 CR ⁴ N N CR ⁵ CR ⁵ N N IA-49 N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ CR ⁵ IA-50 N CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ IA-51 N CR ⁴ N CR ⁵ N CR ⁵ CR ⁵ IA-52 N CR ⁴ N CR ⁵ CR ⁵ N CR ⁵ IA-53 N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ N IA-54 N CR ⁴ N N N CR ⁵ CR ⁵ IA-55 N CR ⁴ N CR ⁵ N N CR ⁵ IA-56 N CR ⁴ N CR ⁵ CR ⁵ N N

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein X is S.

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein X is O.

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein each R ^{4 is} independently H, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or S(O) _p (C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl).

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein each R ^{4 is} independently H, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, second butyl, isobutyl or tertiary butyl.

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein each R ^{4 is} independently H, CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ or -CF ₂ CF ₃ .

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein each R ^{4 is} independently H, methoxy, ethoxy, propoxy, or butoxy.

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein each R ^{4 is} independently H, -OCF ₃ or -SCF ₃ .

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein each R ^{5 is} independently H, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or S(O) _p (C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl).

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein each R ^{5 is} independently H, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, second butyl, isobutyl or tertiary butyl.

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein each R ^{5 is} independently H, CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ or -CF ₂ CF ₃ .

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein each R ^{5 is} independently H, methoxy, ethoxy, propoxy, or butoxy.

In some embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein each R ^{5 is} independently H, -OCF ₃ or -SCF ₃ .

In other embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein R ² and R ^{10 are} independently H or C ₁ -C ₃ alkyl.

In other embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein a is 1, W is CH ₂ , and Z is O.

In other embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein R ¹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy-C ₁ -C ₆ alkane Group, C ₁ -C ₆ alkoxy group -C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkoxy group -C ₁ -C ₆ alkyl group, amino group -C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, optionally substituted C ₃ -C ₈ cycloalkyl, as appropriate the substituted 3-7 heterocyclyl group or -NR ^a R ^b, wherein R ^a and R ^b are independently H or optionally substituted alkyl of C ₁ -C _6; or R ^a and R ^b therewith The connected nitrogens together form a 3-membered, 4-membered, 5-membered or 6-membered heterocyclic group, which may include one to three additional heteroatoms selected from the group consisting of N, O, and S, and optionally substituted.

In other embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein R ³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, optionally substituted C _3- C ₈ cycloalkyl, optionally substituted 3- to 7-membered heterocyclic group containing one to three heteroatoms selected from the group consisting of N, O and S, optionally substituted phenyl, optionally substituted 5-membered to 10-membered heteroaryl, 5-membered to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5-membered to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5-membered to 11-membered spirocyclic carbocyclyl - carbocyclyl, 5-11 spiro carbocyclic group - heterocyclyl or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ Haloalkyl; or R ^a and R ^b may form a 3-membered, 4-membered, 5-membered or 6-membered heterocyclic group together with the nitrogen to which they are attached, and the heterocyclic group may include one to three selected from N, O and S The additional heteroatoms of the group can be substituted as appropriate.

In other embodiments, the present invention provides compounds of formula IA-1 to formula IA-56, wherein X is S, R ² and R ^{10 are} independently H or C ₁ -C ₃ alkyl; W is CH ₂ , Z Is O, and a is 1.

In other embodiments, the present invention provides the compound of formula IA-1 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl group substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently H or a halo; and R ² is H or a C ₁ -C ₃ alkyl group.

In other embodiments, the present invention provides the compound of formula IA-1 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl group substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently H or a halo; and R ² is H or a C ₁ -C ₃ alkyl group.

In other embodiments, the present invention provides the compound of formula IA-9 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl group substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently H or a halo; and R ² is H or a C ₁ -C ₃ alkyl group.

In other embodiments, the present invention provides the compound of formula IA-9 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl group substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently H or a halo; and R ² is H or a C ₁ -C ₃ alkyl group.

In other embodiments, the present invention provides the compound of formula IA-17 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 A phenyl group substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently H or a halo; and R ² is H or a C ₁ -C ₃ alkyl group.

In other embodiments, the present invention provides the compound of formula IA-17 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl group substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently H or a halo; and R ² is H or a C ₁ -C ₃ alkyl group.

In other embodiments, the present invention provides the compound of formula IA-25 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl group substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently H or a halo; and R ² is H or a C ₁ -C ₃ alkyl group.

In other embodiments, the present invention provides the compound of formula IA-25 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl group substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently H or a halo; and R ² is H or a C ₁ -C ₃ alkyl group.

In other embodiments, the present invention provides the compound of formula IA-49 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 A phenyl group substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently H or a halo; and R ² is H or a C ₁ -C ₃ alkyl group.

In other embodiments, the present invention provides the compound of formula IA-49 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl group substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently H or a halo; and R ² is H or a C ₁ -C ₃ alkyl group.

表2 式 Y¹ Y² Y³ Y^2' Y^3' Y^4' Y^5' IB-1 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ IB-2 CR⁴ CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ IB-3 CR⁴ CR⁴ CR⁴ CR⁵ N CR⁵ CR⁵ IB-4 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ N CR⁵ IB-5 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ N IB-6 CR⁴ CR⁴ CR⁴ N N CR⁵ CR⁵ IB-7 CR⁴ CR⁴ CR⁴ CR⁵ N N CR⁵ IB-8 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ N N IB-9 N CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ IB-10 N CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ IB-11 N CR⁴ CR⁴ CR⁵ N CR⁵ CR⁵ IB-12 N CR⁴ CR⁴ CR⁵ CR⁵ N CR⁵ IB-13 N CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ N IB-14 N CR⁴ CR⁴ N N CR⁵ CR⁵ IB-15 N CR⁴ CR⁴ CR⁵ N N CR⁵ IB-16 N CR⁴ CR⁴ CR⁵ CR⁵ N N IB-17 CR⁴ N CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ IB-18 CR⁴ N CR⁴ N CR⁵ CR⁵ CR⁵ IB-19 CR⁴ N CR⁴ CR⁵ N CR⁵ CR⁵ 1B-20 CR⁴ N CR⁴ CR⁵ CR⁵ N CR⁵ IB-21 CR⁴ N CR⁴ CR⁵ CR⁵ CR⁵ N IB-22 CR⁴ N CR⁴ N N CR⁵ CR⁵ IB-23 CR⁴ N CR⁴ CR⁵ N N CR⁵ IB-24 CR⁴ N CR⁴ CR⁵ CR⁵ N N IB-25 CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ CR⁵ IB-26 CR⁴ CR⁴ N N CR⁵ CR⁵ CR⁵ IB-27 CR⁴ CR⁴ N CR⁵ N CR⁵ CR⁵ IB-28 CR⁴ CR⁴ N CR⁵ CH N CR⁵ IB-29 CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ N IB-30 CR⁴ CR⁴ N N N CR⁵ CR⁵ IB-31 CR⁴ CR⁴ N CR⁵ N N CR⁵ IB-32 CR⁴ CR⁴ N CR⁵ CR⁵ N N IB-33 N N CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ IB-34 N N CR⁴ N CR⁵ CR⁵ CR⁵ IB-35 N N CR⁴ CR⁵ N CR⁵ CR⁵ IB-36 N N CR⁴ CR⁵ CR⁵ N CR⁵ IB-37 N N CR⁴ CR⁵ CR⁵ CR⁵ N IB-38 N N CR⁴ N N CR⁵ CR⁵ IB-39 N N CR⁴ CR⁴ N N CR⁵ IB-40 N N CR⁴ CR⁵ CR⁵ N N IB-41 CR⁴ N N CR⁵ CR⁵ CR⁵ CR⁵ IB-42 CR⁴ N N N CR⁵ CR⁵ CR⁵ IB-43 CR⁴ N N CR⁵ N CR⁵ CR⁵ IB-44 CR⁴ N N CR⁵ CR⁵ N CR⁵ IB-45 CR⁴ N N CR⁵ CR⁵ CR⁵ N IB-46 CR⁴ N N N N CR⁵ CR⁵ IB-47 CR⁴ N N CR⁵ N N CR⁵ IB-48 CR⁴ N N CR⁵ CR⁵ N N IB-49 N CR⁴ N CR⁵ CR⁵ CR⁵ CR⁵ IB-50 N CR⁴ N N CR⁵ CR⁵ CR⁵ IB-51 N CR⁴ N CR⁵ N CR⁵ CR⁵ IB-52 N CR⁴ N CR⁵ CR⁵ N CR⁵ IB-53 N CR⁴ N CR⁵ CR⁵ CR⁵ N IB-54 N CR⁴ N N N CR⁵ CR⁵ IB-55 N CR⁴ N CR⁵ N N CR⁵ IB-56 N CR⁴ N CR⁵ CR⁵ N N In other embodiments, the present invention provides compounds of formula (IB) shown below, wherein the variables R ¹ , R ² , R ⁴ , R ⁵ , X, W, Z, R ¹⁰ and a are as described above for formula (I) As defined; each R ⁹ is cyano, halo, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy , C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ haloalkynyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkane Group, C ₁ -C ₆ haloalkoxy-C ₁ -C ₆ alkyl group, optionally substituted phenyl group, optionally substituted phenoxy group, optionally substituted 5-membered or 6-membered heteroaryl group , Optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkyloxy, optionally containing one to three heteroatoms selected from the group consisting of N, O and S Situation Substituted 3-membered to 7-membered heterocyclic group, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxy Carbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ haloalkylaminocarbonyl, di-C ₁ -C ₆ alkylaminocarbonyl, di-C ₁ -C ₆ Haloalkylaminocarbonyl, -SO _p (optionally substituted C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl) (where p is 0, 1 or 2), SF ₅ or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or R ^a and R ^b may be taken together with the nitrogen to which they are attached 3, 4 , 5-membered, 6-membered, 7-membered, or 8-membered heterocyclic group, the heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O and S and may be substituted as appropriate; m is 0, 1 2, 3 or 4; and ^{Y 1, Y 2, Y 3} , Y 2 ', Y 3', Y 4 ' and Y ^5' as shown in table 2:

Table 2 formula Y ¹ Y ² Y ³ Y ^2' Y ^3' Y ^4' Y ^5' IB-1 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ IB-2 CR ⁴ CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ IB-3 CR ⁴ CR ⁴ CR ⁴ CR ⁵ N CR ⁵ CR ⁵ IB-4 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ N CR ⁵ IB-5 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ N IB-6 CR ⁴ CR ⁴ CR ⁴ N N CR ⁵ CR ⁵ IB-7 CR ⁴ CR ⁴ CR ⁴ CR ⁵ N N CR ⁵ IB-8 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ N N IB-9 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ IB-10 N CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ IB-11 N CR ⁴ CR ⁴ CR ⁵ N CR ⁵ CR ⁵ IB-12 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ N CR ⁵ IB-13 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ N IB-14 N CR ⁴ CR ⁴ N N CR ⁵ CR ⁵ IB-15 N CR ⁴ CR ⁴ CR ⁵ N N CR ⁵ IB-16 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ N N IB-17 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ IB-18 CR ⁴ N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ IB-19 CR ⁴ N CR ⁴ CR ⁵ N CR ⁵ CR ⁵ 1B-20 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ N CR ⁵ IB-21 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ CR ⁵ N IB-22 CR ⁴ N CR ⁴ N N CR ⁵ CR ⁵ IB-23 CR ⁴ N CR ⁴ CR ⁵ N N CR ⁵ IB-24 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ N N IB-25 CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ CR ⁵ IB-26 CR ⁴ CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ IB-27 CR ⁴ CR ⁴ N CR ⁵ N CR ⁵ CR ⁵ IB-28 CR ⁴ CR ⁴ N CR ⁵ CH N CR ⁵ IB-29 CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ N IB-30 CR ⁴ CR ⁴ N N N CR ⁵ CR ⁵ IB-31 CR ⁴ CR ⁴ N CR ⁵ N N CR ⁵ IB-32 CR ⁴ CR ⁴ N CR ⁵ CR ⁵ N N IB-33 N N CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ IB-34 N N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ IB-35 N N CR ⁴ CR ⁵ N CR ⁵ CR ⁵ IB-36 N N CR ⁴ CR ⁵ CR ⁵ N CR ⁵ IB-37 N N CR ⁴ CR ⁵ CR ⁵ CR ⁵ N IB-38 N N CR ⁴ N N CR ⁵ CR ⁵ IB-39 N N CR ⁴ CR ⁴ N N CR ⁵ IB-40 N N CR ⁴ CR ⁵ CR ⁵ N N IB-41 CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ CR ⁵ IB-42 CR ⁴ N N N CR ⁵ CR ⁵ CR ⁵ IB-43 CR ⁴ N N CR ⁵ N CR ⁵ CR ⁵ IB-44 CR ⁴ N N CR ⁵ CR ⁵ N CR ⁵ IB-45 CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ N IB-46 CR ⁴ N N N N CR ⁵ CR ⁵ IB-47 CR ⁴ N N CR ⁵ N N CR ⁵ IB-48 CR ⁴ N N CR ⁵ CR ⁵ N N IB-49 N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ CR ⁵ IB-50 N CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ IB-51 N CR ⁴ N CR ⁵ N CR ⁵ CR ⁵ IB-52 N CR ⁴ N CR ⁵ CR ⁵ N CR ⁵ IB-53 N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ N IB-54 N CR ⁴ N N N CR ⁵ CR ⁵ IB-55 N CR ⁴ N CR ⁵ N N CR ⁵ IB-56 N CR ⁴ N CR ⁵ CR ⁵ N N

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein X is S.

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein X is O.

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein each R ^{4 is} independently H, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or S(O) _p (C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl).

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein each R ^{4 is} independently H, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, second butyl, isobutyl or tertiary butyl.

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein each R ^{4 is} independently H, CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ or -CF ₂ CF ₃ .

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein each R ^{4 is} independently H, methoxy, ethoxy, propoxy, or butoxy.

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein each R ^{4 is} independently H, -OCF ₃ or -SCF ₃ .

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein each R ^{5 is} independently H, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or S(O) _p (C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl).

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein each R ^{5 is} independently H, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, second butyl, isobutyl or tertiary butyl.

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein each R ^{5 is} independently H, CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ or -CF ₂ CF ₃ .

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein each R ^{5 is} independently H, methoxy, ethoxy, propoxy, or butoxy.

In some embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein each R ^{5 is} independently H, -OCF ₃ or -SCF ₃ .

In other embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein R ² and R ^{10 are} independently H or C ₁ -C ₃ alkyl.

In other embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein R ¹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy-C ₁ -C ₆ alkane Group, C ₁ -C ₆ alkoxy group -C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkoxy group -C ₁ -C ₆ alkyl group, amino group -C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, optionally substituted C ₃ -C ₈ cycloalkyl, as appropriate the substituted 3-7 heterocyclyl group or -NR ^a R ^b, wherein R ^a and R ^b are independently H or optionally substituted alkyl of C ₁ -C _6; or R ^a and R ^b therewith The connected nitrogens together form a 3-membered, 4-membered, 5-membered or 6-membered heterocyclic group, which may include one to three additional heteroatoms selected from the group consisting of N, O, and S, and optionally substituted.

In other embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein R ³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, optionally substituted C _3- C ₈ cycloalkyl, optionally substituted 3- to 7-membered heterocyclic group containing one to three heteroatoms selected from the group consisting of N, O and S, optionally substituted phenyl, optionally substituted 5-membered to 10-membered heteroaryl, 5-membered to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5-membered to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5-membered to 11-membered spirocyclic carbocyclyl - carbocyclyl, 5-11 spiro carbocyclic group - heterocyclyl or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ Haloalkyl; or R ^a and R ^b may form a 3-membered, 4-membered, 5-membered or 6-membered heterocyclic group together with the nitrogen to which they are attached, and the heterocyclic group may include one to three selected from N, O and S The additional heteroatoms of the group can be substituted as appropriate.

In other embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein a is 1, W is CH ₂ , and Z is O.

In other embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein R ^{9 is} independently halo, cyano, nitro, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ Haloalkyl, C ₃ -C ₆ halocycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy or S(O) _p (C ₁ -C ₆ alkyl or C _1- C ₆ haloalkyl), and m is 0, 1, 2 or 3.

In other embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein R ^{9 is} independently halo, and m is 1, 2, or 3.

In other embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein R ^{9 is} independently fluorine or chlorine, and m is 1, 2, or 3.

In other embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein X is S, R ^{9 is} independently halo, and m is 1, 2 or 3, and R ² and R ^{10 are} independently Is H or C ₁ -C ₃ alkyl; W is CH ₂ , Z is O, and a is 1.

In other embodiments, the present invention provides compounds of formula IB-1 to formula IB-56, wherein X is S, R ^{9 is} independently chlorine or fluorine, and m is 1, 2 or 3, and R ² and R ^{10 are} independently Ground is H or C ₁ -C ₃ alkyl; W is CH ₂ , Z is O, and a is 1.

In other embodiments, the present invention provides the compound of formula IB-1 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IB-1 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IB-9 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IB-9 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IB-17 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IB-17 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IB-25 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IB-25 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IB-49 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula (I) B-49 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted independently Phenyl substituted with 1 to 3 halo groups; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently Is halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

表3 式 Y¹ Y² Y³ IC-1 CR⁴ CR⁴ CR⁴ IC-2 N CR⁴ CR⁴ IC-3 CR⁴ N CR⁴ IC-4 CR⁴ CR⁴ N IC-5 N N CR⁴ IC-6 CR⁴ N N IC-7 N CR⁴ N In other embodiments, the present invention provides a compound of formula (IC), wherein the variables R ¹ , R ² , R ⁴ , R ⁵ , W and X are as defined above for formula (I); R ⁹ and m are as defined above for formula (I) Defined by IB; o is 0 ^{, 1 , 2} , 3 or 4; and Y 1, Y 2 and Y ^{3 are} as shown in Table 3:

table 3 formula Y ¹ Y ² Y ³ IC-1 CR ⁴ CR ⁴ CR ⁴ IC-2 N CR ⁴ CR ⁴ IC-3 CR ⁴ N CR ⁴ IC-4 CR ⁴ CR ⁴ N IC-5 N N CR ⁴ IC-6 CR ⁴ N N IC-7 N CR ⁴ N

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein X is S.

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein X is O.

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein each R ^{4 is} independently H, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or S(O) _p (C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl).

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein each R ^{4 is} independently H, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, second butyl, isobutyl, tertiary butyl.

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein each R ^{4 is} independently H, CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ , -CF ₂ CF ₃ .

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein each R ^{4 is} independently H, methoxy, ethoxy, propoxy, or butoxy.

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein each R ^{4 is} independently H, -OCF ₃ or -SCF ₃ .

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein each R ^{5 is} independently halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or S(O) _p (C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl); and o is 0, 1, 2 or 3.

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein each R ^{5 is} independently chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, Second butyl, isobutyl or tertiary butyl; and o is 0, 1, 2 or 3.

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein each R ^{5 is} independently CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ or -CF ₂ CF ₃ ; and o is 0, 1, 2, or 3.

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein each R ^{5 is} independently methoxy, ethoxy, propoxy or butoxy; and o is 0, 1. , 2 or 3.

In some embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein each R ^{5 is} independently -OCF ₃ or -SCF ₃ ; and o is 0, 1, 2, or 3.

In other embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein R ² is H or C ₁ -C ₃ alkyl.

In other embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein R ¹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy-C ₁ -C ₆ alkane Group, C ₁ -C ₆ alkoxy group -C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkoxy group -C ₁ -C ₆ alkyl group, amino group -C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, optionally substituted C ₃ -C ₈ cycloalkyl, as appropriate the substituted 3-7 heterocyclyl group or -NR ^a R ^b, wherein R ^a and R ^b are independently H or optionally substituted alkyl of C ₁ -C _6; or R ^a and R ^b therewith The connected nitrogens together form a 3-membered, 4-membered, 5-membered or 6-membered heterocyclic group, which may include one to three additional heteroatoms selected from the group consisting of N, O, and S, and optionally substituted.

In other embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein R ³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, optionally substituted C _3- C ₈ cycloalkyl, optionally substituted 3- to 7-membered heterocyclic group containing one to three heteroatoms selected from the group consisting of N, O and S, optionally substituted phenyl, optionally substituted 5-membered to 10-membered heteroaryl, 5-membered to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5-membered to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5-membered to 11-membered spirocyclic carbocyclyl - carbocyclyl, 5-11 spiro carbocyclic group - heterocyclyl or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ Haloalkyl; or R ^a and R ^b may form a 3-membered, 4-membered, 5-membered or 6-membered heterocyclic group together with the nitrogen to which they are attached, and the heterocyclic group may include one to three selected from N, O and S The additional heteroatoms of the group can be substituted as appropriate.

In other embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkane Oxy or haloalkoxy, and m is 0, 1, 2 or 3.

In other embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein R ^{9 is} independently halo, and m is 1, 2, or 3.

In other embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein R ^{9 is} independently fluorine or chlorine, and m is 1, 2, or 3.

In other embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein X is S, R ^{9 is} independently halo, and m is 1, 2 or 3, and R ² is H or C ₁ -C ₃ alkyl.

In other embodiments, the present invention provides compounds of formula IC-1 to formula IC-7, wherein X is S, R ^{9 is} independently chlorine or fluorine, and m is 1, 2 or 3, and R ² is H or C ₁ -C ₃ alkyl.

In other embodiments, the present invention provides the compound of formula IC-1 above, wherein R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or Haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IC-2 above, wherein R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or Haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IC-3 above, wherein R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or Haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IC-7 above, wherein R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy or Haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IC-1 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 A phenyl substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently a halo, and o is 0, 1, or 2; R ² is H or a C ₁ -C ₃ alkyl group; R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IC-1 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently a halo, and o is 0, 1, or 2; R ² is H or a C ₁ -C ₃ alkyl group; R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IC-2 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 A phenyl substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently a halo, and o is 0, 1, or 2; R ² is H or a C ₁ -C ₃ alkyl group; R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IC-2 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; R ⁵ is a halo, and o is 0, 1, or 2; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently Ground is halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IC-3 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 A phenyl substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently a halo, and o is 0, 1, or 2; R ² is H or a C ₁ -C ₃ alkyl group; R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IC-3 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently a halo, and o is 0, 1, or 2; R ² is H or a C ₁ -C ₃ alkyl group; R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IC-7 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently a halo, and o is 0, 1, or 2; R ² is H or a C ₁ -C ₃ alkyl group; R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula IC-7 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently A phenyl substituted with a halo; each R ^{4 is} independently H or a halo; each R ^{5 is} independently a halo, and o is 0, 1, or 2; R ² is H or a C ₁ -C ₃ alkyl group; R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

)為單鍵或雙鍵；D為N、C或C-R⁴ ；D¹ 為N、O、-CR⁴ R⁵ 、S(O)_p (其中p為0、1或2)，或D¹ 為CR⁴ R⁵ ，其中R⁴ 及R⁵ 一起形成2員至5員鏈，其視情況與該鏈中之一個雜原子一起形成螺環基團；且Y¹ 、Y² 、Y³ 、Y^2' 、Y^3' 、Y^4' 及Y^5' 如表4中所展示：

表4 式 Y¹ Y² Y³ Y^2' Y^3' Y^4' Y^5' ID-1 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ ID-2 CR⁴ CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ ID-3 CR⁴ CR⁴ CR⁴ CR⁵ N CR⁵ CR⁵ ID-4 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ N CR⁵ ID-5 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ N ID-6 CR⁴ CR⁴ CR⁴ N N CR⁵ CR⁵ ID-7 CR⁴ CR⁴ CR⁴ CR⁵ N N CR⁵ ID-8 CR⁴ CR⁴ CR⁴ CR⁵ CR⁵ N N ID-9 N CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ ID-10 N CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ ID-11 N CR⁴ CR⁴ CR⁵ N CR⁵ CR⁵ ID-12 N CR⁴ CR⁴ CR⁵ CR⁵ N CR⁵ ID-13 N CR⁴ CR⁴ CR⁵ CR⁵ CR⁵ N ID-14 N CR⁴ CR⁴ N N CR⁵ CR⁵ ID-15 N CR⁴ CR⁴ CR⁵ N N CR⁵ ID-16 N CR⁴ CR⁴ CR⁵ CR⁵ N N ID-17 CR⁴ N CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ ID-18 CR⁴ N CR⁴ N CR⁵ CR⁵ CR⁵ ID-19 CR⁴ N CR⁴ CR⁵ N CR⁵ CR⁵ 1D-20 CR⁴ N CR⁴ CR⁵ CR⁵ N CR⁵ ID-21 CR⁴ N CR⁴ CR⁵ CR⁵ CR⁵ N ID-22 CR⁴ N CR⁴ N N CR⁵ CR⁵ ID-23 CR⁴ N CR⁴ CR⁵ N N CR⁵ ID-24 CR⁴ N CR⁴ CR⁵ CR⁵ N N ID-25 CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ CR⁵ ID-26 CR⁴ CR⁴ N N CR⁵ CR⁵ CR⁵ ID-27 CR⁴ CR⁴ N CR⁵ N CR⁵ CR⁵ ID-28 CR⁴ CR⁴ N CR⁵ CH N CR⁵ ID-29 CR⁴ CR⁴ N CR⁵ CR⁵ CR⁵ N ID-30 CR⁴ CR⁴ N N N CR⁵ CR⁵ ID-31 CR⁴ CR⁴ N CR⁵ N N CR⁵ ID-32 CR⁴ CR⁴ N CR⁵ CR⁵ N N ID-33 N N CR⁴ CR⁵ CR⁵ CR⁵ CR⁵ ID-34 N N CR⁴ N CR⁵ CR⁵ CR⁵ ID-35 N N CR⁴ CR⁵ N CR⁵ CR⁵ ID-36 N N CR⁴ CR⁵ CR⁵ N CR⁵ ID-37 N N CR⁴ CR⁵ CR⁵ CR⁵ N ID-38 N N CR⁴ N N CR⁵ CR⁵ ID-39 N N CR⁴ CR⁴ N N CR⁵ ID-40 N N CR⁴ CR⁵ CR⁵ N N ID-41 CR⁴ N N CR⁵ CR⁵ CR⁵ CR⁵ ID-42 CR⁴ N N N CR⁵ CR⁵ CR⁵ ID-43 CR⁴ N N CR⁵ N CR⁵ CR⁵ ID-44 CR⁴ N N CR⁵ CR⁵ N CR⁵ ID-45 CR⁴ N N CR⁵ CR⁵ CR⁵ N ID-46 CR⁴ N N N N CR⁵ CR⁵ ID-47 CR⁴ N N CR⁵ N N CR⁵ ID-48 CR⁴ N N CR⁵ CR⁵ N N ID-49 N CR⁴ N CR⁵ CR⁵ CR⁵ CR⁵ ID-50 N CR⁴ N N CR⁵ CR⁵ CR⁵ ID-51 N CR⁴ N CR⁵ N CR⁵ CR⁵ ID-52 N CR⁴ N CR⁵ CR⁵ N CR⁵ ID-53 N CR⁴ N CR⁵ CR⁵ CR⁵ N ID-54 N CR⁴ N N N CR⁵ CR⁵ ID-55 N CR⁴ N CR⁵ N N CR⁵ ID-56 N CR⁴ N CR⁵ CR⁵ N N In other embodiments, the present invention provides a compound of formula (ID), wherein the variables R ¹ , R ² , R ⁴ , R ⁵ , R ¹⁰ , X, W, Z and a are as defined above for formula (I); R ⁹ and m are as defined above for formula IB; b is 0 or 1; dashed key (

) Is a single bond or a double bond; D is N, C or CR ⁴ ; D ¹ is N, O, -CR ⁴ R ⁵ , S(O) _p (where p is 0, 1 or 2), or D ¹ is CR ⁴ R ⁵ , where R ⁴ and R ⁵ together form a 2-member to 5-member chain, which optionally together with a heteroatom in the chain forms a spiro ring group; and Y ¹ , Y ² , Y ³ , Y ^{2 ', Y 3', Y 4} ' and Y ^5' as shown in table 4:

Table 4 formula Y ¹ Y ² Y ³ Y ^2' Y ^3' Y ^4' Y ^5' ID-1 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ ID-2 CR ⁴ CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ ID-3 CR ⁴ CR ⁴ CR ⁴ CR ⁵ N CR ⁵ CR ⁵ ID-4 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ N CR ⁵ ID-5 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ N ID-6 CR ⁴ CR ⁴ CR ⁴ N N CR ⁵ CR ⁵ ID-7 CR ⁴ CR ⁴ CR ⁴ CR ⁵ N N CR ⁵ ID-8 CR ⁴ CR ⁴ CR ⁴ CR ⁵ CR ⁵ N N ID-9 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ ID-10 N CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ ID-11 N CR ⁴ CR ⁴ CR ⁵ N CR ⁵ CR ⁵ ID-12 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ N CR ⁵ ID-13 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ CR ⁵ N ID-14 N CR ⁴ CR ⁴ N N CR ⁵ CR ⁵ ID-15 N CR ⁴ CR ⁴ CR ⁵ N N CR ⁵ ID-16 N CR ⁴ CR ⁴ CR ⁵ CR ⁵ N N ID-17 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ ID-18 CR ⁴ N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ ID-19 CR ⁴ N CR ⁴ CR ⁵ N CR ⁵ CR ⁵ 1D-20 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ N CR ⁵ ID-21 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ CR ⁵ N ID-22 CR ⁴ N CR ⁴ N N CR ⁵ CR ⁵ ID-23 CR ⁴ N CR ⁴ CR ⁵ N N CR ⁵ ID-24 CR ⁴ N CR ⁴ CR ⁵ CR ⁵ N N ID-25 CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ CR ⁵ ID-26 CR ⁴ CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ ID-27 CR ⁴ CR ⁴ N CR ⁵ N CR ⁵ CR ⁵ ID-28 CR ⁴ CR ⁴ N CR ⁵ CH N CR ⁵ ID-29 CR ⁴ CR ⁴ N CR ⁵ CR ⁵ CR ⁵ N ID-30 CR ⁴ CR ⁴ N N N CR ⁵ CR ⁵ ID-31 CR ⁴ CR ⁴ N CR ⁵ N N CR ⁵ ID-32 CR ⁴ CR ⁴ N CR ⁵ CR ⁵ N N ID-33 N N CR ⁴ CR ⁵ CR ⁵ CR ⁵ CR ⁵ ID-34 N N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ ID-35 N N CR ⁴ CR ⁵ N CR ⁵ CR ⁵ ID-36 N N CR ⁴ CR ⁵ CR ⁵ N CR ⁵ ID-37 N N CR ⁴ CR ⁵ CR ⁵ CR ⁵ N ID-38 N N CR ⁴ N N CR ⁵ CR ⁵ ID-39 N N CR ⁴ CR ⁴ N N CR ⁵ ID-40 N N CR ⁴ CR ⁵ CR ⁵ N N ID-41 CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ CR ⁵ ID-42 CR ⁴ N N N CR ⁵ CR ⁵ CR ⁵ ID-43 CR ⁴ N N CR ⁵ N CR ⁵ CR ⁵ ID-44 CR ⁴ N N CR ⁵ CR ⁵ N CR ⁵ ID-45 CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ N ID-46 CR ⁴ N N N N CR ⁵ CR ⁵ ID-47 CR ⁴ N N CR ⁵ N N CR ⁵ ID-48 CR ⁴ N N CR ⁵ CR ⁵ N N ID-49 N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ CR ⁵ ID-50 N CR ⁴ N N CR ⁵ CR ⁵ CR ⁵ ID-51 N CR ⁴ N CR ⁵ N CR ⁵ CR ⁵ ID-52 N CR ⁴ N CR ⁵ CR ⁵ N CR ⁵ ID-53 N CR ⁴ N CR ⁵ CR ⁵ CR ⁵ N ID-54 N CR ⁴ N N N CR ⁵ CR ⁵ ID-55 N CR ⁴ N CR ⁵ N N CR ⁵ ID-56 N CR ⁴ N CR ⁵ CR ⁵ N N

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein X is S.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein X is O.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein the dashed bond is a single bond.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein the dashed bond is a double bond.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein D is CH, C-halo or N.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein D is C, CH, C-F or N.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein D ¹ is CR ⁴ R ⁵ , wherein R ⁴ and R ⁵ together form a 2- to 5-member chain, which may be combined with the One heteroatom in the chain together forms a spirocyclic group.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein D ¹ is CH ₂ , independently C-(halo) ₂ , CH(C ₁ -C ₃ alkyl) or CH (C ₁ -C ₃ haloalkyl).

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein D ¹ is CH ₂ , independently CF ₂ , CH(CH ₃ ), or CH(CF ₃ ).

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein D ¹ is O, S, S(O), or S(O) ₂ .

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein D is CH or C-halo; and D ¹ is CH ₂ .

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein D is N; and D ¹ is CH ₂ , O, or S.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein the dashed line is a double bond; D is C; and D ¹ is CH ₂ , CF ₂ , O, or S.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein D is N; and D ¹ is CR ⁴ R ⁵ , wherein R ⁴ and R ⁵ together form a 2- to 4-membered chain, It optionally forms a spirocyclic group with one oxygen in the chain.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein D is CH; and D ¹ is CR ⁴ R ⁵ , wherein R ⁴ and R ⁵ together form a 2- to 4-membered chain, It optionally forms a spirocyclic group with one oxygen in the chain.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein D is C, and the dashed bond represents a double bond; and D ¹ is CR ⁴ R ⁵ , wherein R ⁴ and R ⁵ together form A 2- to 4-membered chain, which optionally forms a spirocyclic group with one oxygen in the chain.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{4 is} independently H, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or S(O) _p (C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl).

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{4 is} independently H, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl , Second butyl, isobutyl, tertiary butyl.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{4 is} independently H, CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ , -CF ₂ CF ₃ .

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{4 is} independently H, methoxy, ethoxy, propoxy, or butoxy.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{4 is} independently H, -OCF ₃ or -SCF ₃ .

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{5 is} independently H, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or S(O) _p (C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl).

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{5 is} independently H, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl , Second butyl, isobutyl, tertiary butyl.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{5 is} independently H, CF ₃ , -CH ₂ CF ₃ , -CHFCF ₃ , -CF ₂ CF ₃ .

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{5 is} independently H, methoxy, ethoxy, propoxy, or butoxy.

In some embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{5 is} independently H, -OCF ₃ or -SCF ₃ .

In other embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ² is H or C ₁ -C ₃ alkyl.

In other embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ¹ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy-C ₁ -C ₆ alkane Group, C ₁ -C ₆ alkoxy group -C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkoxy group -C ₁ -C ₆ alkyl group, amino group -C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, optionally substituted C ₃ -C ₈ cycloalkyl, as appropriate the substituted 3-7 heterocyclyl group or -NR ^a R ^b, wherein R ^a and R ^b are independently H or optionally substituted alkyl of C ₁ -C _6; or R ^a and R ^b therewith The connected nitrogens together form a 3-membered, 4-membered, 5-membered or 6-membered heterocyclic group, which may include one to three additional heteroatoms selected from the group consisting of N, O, and S, and optionally substituted.

In other embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkane Oxy or haloalkoxy, m is 0, 1, 2 or 3, and b is 0 or 1.

In other embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{9 is} independently halo, and m is 1, 2, or 3.

In other embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein R ^{9 is} independently fluorine or chlorine, and m is 1, 2, or 3.

In other embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein X is S, R ^{9 is} independently halo, and m is 1, 2 or 3, and R ² is H or C ₁ -C ₃ alkyl.

In other embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein X is S, R ^{9 is} independently chlorine or fluorine, and m is 1, 2 or 3, and R ² is H or C ₁ -C ₃ alkyl.

In other embodiments, the present invention provides compounds of formula ID-1 to formula ID-56, wherein X is S, and R ^{9 is} independently halo, cyano, nitro, cycloalkyl, haloalkyl, halo ring Alkyl, alkoxy or haloalkoxy; D is N or CH; D ¹ is NH, O or CH ₂ ; b is 0 or 1; and m is 0, 1, 2 or 3.

In other embodiments, the present invention provides the compound of formula ID-1 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula ID-1 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula ID-9 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula ID-9 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally 1 to 3 Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula ID-17 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula ID-17 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula ID-25 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula ID-25 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula ID-49 above, wherein X is S; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In other embodiments, the present invention provides the compound of formula ID-49 above, wherein X is O; R ¹ is optionally substituted C ₁ -C ₃ alkyl; R ³ is optionally substituted by 1 to 3 independently Phenyl substituted with a halo; each R ^{4 is} independently H or halo; each R ^{5 is} independently H or halo; R ² is H or C ₁ -C ₃ alkyl; R ^{9 is} independently halo , Cyano, nitro, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, or haloalkoxy, and m is 0, 1, 2, or 3.

In the above Table 1, Table 2 or Table any of the embodiments in one of the ^{4, Y 2 ', Y 3'} , Y 4 ', Y 5' in the each is CH.

In Table 1 above, in the embodiment 4 according to any one of the embodiments in Table 2 ^{or, Y 2 ', Y 3'} , Y 4 ' and Y ^5' is one of those CR ^5, wherein R ⁵ is non- Hydrogen substituent.

In Table 1 above, in the embodiment 4 according to any one of the embodiments in Table 2 or, Y ^{2 ',} Y ^3' both, Y ^{4 'and} Y ^5' is in the CR ^5, wherein each R ⁵ is independently Ground is a non-hydrogen substituent.

In Table 1 above, in the embodiment 4 according to any one of the embodiments in Table 2 ^{or, Y 2 ', Y 3'} , Y 4 ' and Y ^5' is in the three CR ^5, wherein each R ⁵ is independently Ground is a non-hydrogen substituent.

In Table 1 above, in the embodiment 4 according to any one of the embodiments in Table 2 ^{or, Y 2 ', Y 3'} , Y 4 ' and Y ^5' of all the four by key CR ^5, wherein each R ^{5 is} independently a non-hydrogen substituent.

In any of the embodiments in Table 1 to Table 4 above, each of Y ¹ , Y ² and Y ³ is CH.

In any of the embodiments in Table 1 to Table 4 above, one of Y ¹ , Y ² and Y ³ is CR ⁴ , wherein R ^{4 is a} non-hydrogen substituent.

In any of the embodiments in Table 1 to Table 4 above, two of Y ¹ , Y ² and Y ³ are CR ⁴ , wherein each R ^{4 is} independently a non-hydrogen substituent.

In any of the embodiments in Table 1 to Table 4 above, three of ^{Y 1} , Y ² and Y ^{3 are CR 4} , wherein each R ^{4 is} independently a non-hydrogen substituent.

In the above Table 1, Table 2 or Table according to any of the embodiments of one embodiment ^{4, Y 2 ', Y 3'} , Y 4 ' and Y ^5' is one of those C- halo.

In the above Table 1, Table 2 or Table according to any of the embodiments of one embodiment ^{4, Y 2 ', Y 3'} , both Y ^{4 'and} Y ^5' is in the C- halo.

In the above Table 1, Table 2 or Table according to any of the embodiments of one embodiment ^{4, Y 2 ', Y 3'} , Y 4 ' and Y ^5' is in the three C- halo.

In any of the embodiments in Table 1 to Table 4 above, one of Y ¹ , Y ² and Y ³ is C-halogen.

In any of the embodiments in Table 1 to Table 4 above, two of Y ¹ , Y ² and Y ³ are C-halogens.

In any of the embodiments in Table 1 to Table 4 above ^{, three of Y 1} , Y ² and Y ³ are C-halogens.

In Table 1 above, any one of the fourth embodiment in one embodiment of Table 2 ^{or, Y 2 ', Y 3'} , Y 4 ' and Y ^5' is one of those C-Cl or CF.

In Table 1 above, any one of the fourth embodiment in one embodiment of Table 2 or, Y ^{2 ',} Y ^3' both, Y ^{4 'and} Y ^5' is independently of the C-Cl or CF.

In Table 1 above, any one of the fourth embodiment in one embodiment of Table 2 ^{or, Y 2 ', Y 3'} , Y 4 ' and Y ^5' is in the three C-Cl or CF.

In any of the embodiments in Table 1 to Table 4 above, one of Y ¹ , Y ² and Y ³ is C-Cl or CF.

In any of the embodiments in Table 1 to Table 4 above, two of Y ¹ , Y ² and Y ³ are independently C-Cl or CF.

In any of the embodiments in Table 1 to Table 4 above, three of Y ¹ , Y ² and Y ³ are independently C-Cl or CF.

In any of the embodiments in Table 1, Table 2, or Table 4 above, a is 1, W is -CH ₂ -, and Z is O.

In any of the embodiments in Table 1 to Table 4 above, R ¹ is a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkenyl group, a C ₁ -C ₄ cycloalkyl group, an amine group, C ₁ -C ₄ alkylamino, di(C ₁ -C ₄ alkyl)amino, N-morpholinyl, piperanyl, tetrahydropiperanyl or dihydropiperanyl.

In any of the examples in Table 1 to Table 4 above, one, two, or three R ⁴ are hydrogen.

In any of the embodiments in Table 1 to Table 4 above, R ⁴ and the other R ^{4 are} independently halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ cycloalkyl, amino, C ₁ -C ₄ alkylamino, di(C ₁ -C ₄ alkyl)amino or optionally substituted by halo or C ₁ -C ₄ alkyl 1 Second or second phenyl.

In any of the embodiments in Table 1 to Table 4 above, R ⁵ and the other R ^{5 are} independently halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ cycloalkyl, amino, C ₁ -C ₄ alkylamino, di(C ₁ -C ₄ alkyl)amino or optionally substituted by halo or C ₁ -C ₄ alkyl 1 Second or second phenyl.

在該表中縮寫為「環系統」，且表示以下基團：

環系統A；

環系統B；

環系統C；

環系統D；

環系統E；

環系統F；

環系統G；

環系統H；

環系統I；及

環系統K。In other embodiments, the present invention includes the compounds of formula (I) shown in Table 5 below, wherein Y1, Y2, Y3, L, X, R1, and R3 are shown in the table; both R ² and R ^2' Are both hydrogen; Q is oxygen; and the group:

It is abbreviated as "Ring System" in this table and represents the following groups:

Ring system A;

Ring system B;

Ring system C;

Ring system D;

Ring system E;

Ring system F;

Ring system G;

Ring system H;

Ring System I; and

Ring system K.

； 2-OH-丙-2-基表示基團

；且 2-F-丙-2-基表示基團

。

式(I) 表5 化合物編號 Y¹ Y² Y³ L X R¹ R³ 環系統 309 N CH CF L1 S i -Pr 3,5-二-Cl-Ph A 264-0 CH N CH L1 S 2-OH-丙-2-基 3,5-二-Cl-Ph A 310 N CH CCl L1 S i -Pr 3,5-二-F-Ph A 347 N CH CH L1 S i -Pr 2,3,5-三-F-Ph A 348 N CH CH L1 S i -Pr 2,3,5-三-F-Ph B 338 N CH CF L1 S t- Bu 3,5-二-Cl-Ph B 336 N CH CF L1 S t- Bu 3,5-二-Cl-Ph B 122 N CH CH L1 S

3,5-二-F-Ph B 263-8 N CH CF L1 S 2-OH-丙-2-基 3,5-二-Cl-Ph A 263 N CH CF L1 S 2-F-丙-2-基 3,5-二-Cl-Ph A 210 N CH CH L1 S t- Bu    3,5-二-F-Ph A 204 N CH CF L1 S i -Pr 3,5-二-F-Ph A 211 N CH CH L1 S i -Pr 3,5-二-Cl-Ph B    311 N CH CH L1 S 2-F-丙-2-基 3,5-二-F-Ph A 259-5 N CH CH L1 S 2-OH-丙-2-基    3,5-二-Cl-Ph B 257 N CH CH L1 S i -Pr 3,5-二-F-Ph B 300 N CH CF L1 S 2-F-丙-2-基 3,5-二-F-Ph B 264 CH N CH L1 S 2-F-丙-2-基 3,5-二-Cl-Ph A 309 N CH CF L1 S i -Pr 3,5-二-Cl-Ph A 259 N CH CH L1 S 2-F-丙-2-基 3,5-二-Cl-Ph B 285 N CH CH L1 S 丙-1-烯-2-基 3,5-二-Cl-Ph A 260 N CH CF L1 S i -Pr 3,5-二-F-Ph B 102 CH CH CH L1 S

3,5-二-F-Ph A 212 N CH CH L1 S 2-F-丙-2-基 3,5-二-Cl-Ph A 119 N CH CH L1 S 丙-1-烯-2-基 3,5-二-F-Ph A 120 N CH CH L1 S i -Pr 3,5-二-F-Ph A 207 N CH CH L1 S i -Pr 3-F-Ph A 258 N CH CH L1 S i -Pr 3,5-二-Cl-Ph B 212-0 N CH CH L1 S 2-OH-丙-2-基 3,5-二-Cl-Ph A 128 CH N CH L1 S i -Pr 3,5-二-F-Ph A 337 N CH CF L1 S t- Bu 3,5-二-F-Ph B 268-4 N CH CH L1 S 2-OH-丙-2-基

A 234 N CH C-OMe L1 S i -Pr

A 254 N CH CH L1 S i -Pr 3,5-二-F-Ph C 268 N CH CH L1 S 2-F-丙-2-基

A 218 CH N CH L1 S i -Pr

A 220 N CH CH L1 S i -Pr

A 252 N CH CH L1 S i -Pr 3,5-二-F-Ph D 209 N CH CH L1 S i -Pr 2,6-二-F-Ph A 253 N CH CH L1 S i -Pr 3,5-二-F-Ph E 246 N CH CH L1 S i -Pr

A 222 N CH CH L1 S i -Pr 環戊基 A 206 N CH CH L1 S i -Pr 2,3-二-Cl-Ph A 255 N CH CH L1 S i -Pr

A 255-0 N CH CH L1 S i -Pr

A 203 N CH CH L1 S i -Pr 2,3,6-三-F-Ph A 256 N CH CH L1 S 丙-1-烯-2-基 3,5-二-F-Ph B 302 N CH CH L1 S i -Pr -CF₃ A 301 N CH CH L1 S i -Pr t -Bu A 238 N CH CH L1 S -CF₂ CF₃ 3,5-二-F-Ph A 243 N CH CH L1 S i -Pr

A 213 N CH CH L1 S i -Pr

A 236 N CH CH L1 S -CF₃ 3,5-二-F-Ph A 201 N CH CH L1 S i -Pr 4-F-2,6-二-Me-Ph A 199 N CH CH L1 S 2-OH-丙-2-基 3,5-二-F-Ph A 205 N CH CH L1 S -CHF₂ 3,5-二-F-Ph A 229 N CH CH L1 S i -Pr

A 223 N CH CH L1 S i -Pr 環己基 A 224 N CH CH L1 S -N(CH₃ )₂ 環己基 A 115 N CH N L1 S 丙-1-烯-2-基 3,5-二-F-Ph A 116 N CH N L1 S i -Pr 3,5-二-F-Ph A 126 CH CH N L1 S

3,5-二-F-Ph A 125 CH CH N L1 S -N(CH₃ )₂ 3,5-二-F-Ph A 127 CH N CH L1 S 丙-1-烯-2-基 3,5-二-F-Ph A 129 CH N CH L1 S -N(CH₃ )₂ 3,5-二-F-Ph A 102-1 CH CH CH L1 S

3,5-二-F-Ph A 101 CH CH CH L1 S

3,5-二-F-Ph A 090 CH CH CH L1 S i -Pr 3,5-二-F-Ph A 130 CH N CH L1 S

3,5-二-F-Ph A 121 N CH CH L1 S -N(CH₃ )₂ 3,5-二-F-Ph A 026 CH CH CH L1 O i -Pr 3,5-二-Cl-Ph A 029 CH CH CH L1 O i -Pr 2,6-二-F-Ph A 030 C-i -Pr CH CH L1 O H 3,5-二-Cl-Ph A 027 CH CH CH L1 O

3,5-二-Cl-Ph A 098 CH CH C(3,5-二-F-Ph) L1 S 丙-1-烯-2-基    H A 100 CH CH C(3,5-二-F-Ph) L1 S -N(CH₃ )₂ H A 099 CH CH C(3,5-二-F-Ph) L1 S i -Pr H A 28 CH CH CH L1 O i -Pr 3,5-二-Cl-Ph F 92 CH CH CH L1 S 丙-1-烯-2-基 3,5-二-F-Ph A 83 CH CH CH L1 S -N(CH₃ )₂ 3,5-二-F-Ph A 239-INT-1 N N CH L1 S 丙-1-烯-2-基 3,5-二-F-Ph A 239 N N CH L1 S i -Pr 3,5-二-F-Ph A 117 N CH N L1 S -N(CH₃ )₂ 3,5-二-F-Ph A 226-3 N CH CH L1 S -N(CH₃ )₂ -C(O)CH₃ A 259-4 N CH CH L1 S -C(O)CH₃ 3,5-二-Cl-Ph B 221 N CH CH L1 S i -Pr -CH(CH₃ )CH₂ -CH(CH₃ )₂ A 319 N CH CF L2 S i -Pr 3,5-二-Cl-Ph A 309 N CH CF L1 S i -Pr 3,5-二-Cl-Ph A 115-INT-3 N CH N L1 S Br 3,5-二-F-Ph A 237 N C-CF₃ N L1 S i -Pr 3,5-二-F-Ph A 225-0 N CH CH L1 S -N(CH₃ )₂

A 226 N CH CH L1 S -N(CH₃ )₂ -CH(CH₃ )CH₂ -CH(CH₃ )₂ A 240 N CH CH L1 S i -Pr

A 241 N CH CH L1 S i -Pr

A 216 N CH CH L1 S

A 208 N CH CH L1 S i -Pr 2-Cl-6-F-Ph A 230 N CH CH L1 S -N(CH₃ )₂

A 232 N CH CH L1 S i -Pr

A 228 N CH CH L1 S -N(CH₃ )₂

A 250 N CH CH L1 S i -Pr

A 219 CH N CH L1 S i -Pr

A 262 N CH CH L1 S i -Pr 3,5-二-F-Ph G 249 N CH CH L1 S i -Pr

A 247 N CH CH L1 S i -Pr

A 237 N C-CF₃ N L1 S 丙-1-烯-2-基 3,5-二-F-Ph A 251 N CH CH L1 S i -Pr 3,5-二-F-Ph H 215 N C-CF₃ CH L1 S i -Pr 3,5-二-Cl-Ph A 231 N CH CH L1 S i -Pr

A 225 N CH CH L1 S -N(CH₃ )₂

A 253-0 N CH CH L1 S i -Pr 3,5-二-F-Ph I 245 N CH CH L1 S i -Pr

A 214 N CH CH L1 S i -Pr

A 211-0 N CH CH L1 S i -Pr 3-Cl-5-(3,5-二-Cl-Ph)-Ph A 248 N CH CH L1 S i -Pr

A 118 N CH N L1 S

3,5-二-F-Ph A 202 N CH CH L1 S i -Pr 4-F-Ph A 242 N CH CH L1 S i -Pr

A 261 N CH CH L1 S i -Pr 3,5-二-F-Ph K 217 N CH CH L1 S

A 227 N CH CH L1 S -N(CH₃ )₂

A 124 CH CH N L1 S i -Pr 3,5-二-F-Ph A 123 CH CH N L1 S 丙-1-烯-2-基 3,5-二-F-Ph A In Table 5, the expression "3,5-Di-F-Ph" means 3,5-difluorophenyl; "3,5-Di-Cl-Ph" means 3,5-dichlorophenyl; "2 ,3,5-Tri-F-Ph" means 2,3,5-trifluorophenyl; "3-F-Ph" means 3-fluorophenyl; "2,6-di-F-Ph" means 2 ,6-Difluorophenyl; "2,3-di-Cl-Ph" means 2,3-dichlorophenyl; "2,3,6-tri-F-Ph" means 2,3,6-tri Fluorophenyl; "4-F-2,6-Di-Me-Ph" means 4-fluoro-2,6-dimethylphenyl; "2-Cl-6-F-Ph" means 2-chloro- 6-fluorophenyl; "3-Cl-5-(3,5-di-Cl-Ph)-Ph" means 3-chloro-5-(3,5-dichlorophenyl)phenyl; etc.; Pro-1-en-2-yl represents a group

; 2-OH-prop-2-yl represents a group

; And 2-F-prop-2-yl represents a group

.

Formula (I) Table 5 Compound number Y ¹ Y ² Y ³ L X R ¹ R ³ Ring system 309 N CH CF L1 S i -Pr 3,5-Di-Cl-Ph A 264-0 CH N CH L1 S 2-OH-prop-2-yl 3,5-Di-Cl-Ph A 310 N CH CCl L1 S i -Pr 3,5-Di-F-Ph A 347 N CH CH L1 S i -Pr 2,3,5-Tri-F-Ph A 348 N CH CH L1 S i -Pr 2,3,5-Tri-F-Ph B 338 N CH CF L1 S t- Bu 3,5-Di-Cl-Ph B 336 N CH CF L1 S t- Bu 3,5-Di-Cl-Ph B 122 N CH CH L1 S

3,5-Di-F-Ph B 263-8 N CH CF L1 S 2-OH-prop-2-yl 3,5-Di-Cl-Ph A 263 N CH CF L1 S 2-F-prop-2-yl 3,5-Di-Cl-Ph A 210 N CH CH L1 S t- Bu 3,5-Di-F-Ph A 204 N CH CF L1 S i -Pr 3,5-Di-F-Ph A 211 N CH CH L1 S i -Pr 3,5-Di-Cl-Ph B 311 N CH CH L1 S 2-F-prop-2-yl 3,5-Di-F-Ph A 259-5 N CH CH L1 S 2-OH-prop-2-yl 3,5-Di-Cl-Ph B 257 N CH CH L1 S i -Pr 3,5-Di-F-Ph B 300 N CH CF L1 S 2-F-prop-2-yl 3,5-Di-F-Ph B 264 CH N CH L1 S 2-F-prop-2-yl 3,5-Di-Cl-Ph A 309 N CH CF L1 S i -Pr 3,5-Di-Cl-Ph A 259 N CH CH L1 S 2-F-prop-2-yl 3,5-Di-Cl-Ph B 285 N CH CH L1 S Prop-1-en-2-yl 3,5-Di-Cl-Ph A 260 N CH CF L1 S i -Pr 3,5-Di-F-Ph B 102 CH CH CH L1 S

3,5-Di-F-Ph A 212 N CH CH L1 S 2-F-prop-2-yl 3,5-Di-Cl-Ph A 119 N CH CH L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 120 N CH CH L1 S i -Pr 3,5-Di-F-Ph A 207 N CH CH L1 S i -Pr 3-F-Ph A 258 N CH CH L1 S i -Pr 3,5-Di-Cl-Ph B 212-0 N CH CH L1 S 2-OH-prop-2-yl 3,5-Di-Cl-Ph A 128 CH N CH L1 S i -Pr 3,5-Di-F-Ph A 337 N CH CF L1 S t- Bu 3,5-Di-F-Ph B 268-4 N CH CH L1 S 2-OH-prop-2-yl

A 234 N CH C-OMe L1 S i -Pr

A 254 N CH CH L1 S i -Pr 3,5-Di-F-Ph C 268 N CH CH L1 S 2-F-prop-2-yl

A 218 CH N CH L1 S i -Pr

A 220 N CH CH L1 S i -Pr

A 252 N CH CH L1 S i -Pr 3,5-Di-F-Ph D 209 N CH CH L1 S i -Pr 2,6-Di-F-Ph A 253 N CH CH L1 S i -Pr 3,5-Di-F-Ph E 246 N CH CH L1 S i -Pr

A 222 N CH CH L1 S i -Pr Cyclopentyl A 206 N CH CH L1 S i -Pr 2,3-bis-Cl-Ph A 255 N CH CH L1 S i -Pr

A 255-0 N CH CH L1 S i -Pr

A 203 N CH CH L1 S i -Pr 2,3,6-Tri-F-Ph A 256 N CH CH L1 S Prop-1-en-2-yl 3,5-Di-F-Ph B 302 N CH CH L1 S i -Pr -CF ₃ A 301 N CH CH L1 S i -Pr t -Bu A 238 N CH CH L1 S -CF ₂ CF ₃ 3,5-Di-F-Ph A 243 N CH CH L1 S i -Pr

A 213 N CH CH L1 S i -Pr

A 236 N CH CH L1 S -CF ₃ 3,5-Di-F-Ph A 201 N CH CH L1 S i -Pr 4-F-2,6-Di-Me-Ph A 199 N CH CH L1 S 2-OH-prop-2-yl 3,5-Di-F-Ph A 205 N CH CH L1 S -CHF ₂ 3,5-Di-F-Ph A 229 N CH CH L1 S i -Pr

A 223 N CH CH L1 S i -Pr Cyclohexyl A 224 N CH CH L1 S -N(CH ₃ ) ₂ Cyclohexyl A 115 N CH N L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 116 N CH N L1 S i -Pr 3,5-Di-F-Ph A 126 CH CH N L1 S

3,5-Di-F-Ph A 125 CH CH N L1 S -N(CH ₃ ) ₂ 3,5-Di-F-Ph A 127 CH N CH L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 129 CH N CH L1 S -N(CH ₃ ) ₂ 3,5-Di-F-Ph A 102-1 CH CH CH L1 S

3,5-Di-F-Ph A 101 CH CH CH L1 S

3,5-Di-F-Ph A 090 CH CH CH L1 S i -Pr 3,5-Di-F-Ph A 130 CH N CH L1 S

3,5-Di-F-Ph A 121 N CH CH L1 S -N(CH ₃ ) ₂ 3,5-Di-F-Ph A 026 CH CH CH L1 O i -Pr 3,5-Di-Cl-Ph A 029 CH CH CH L1 O i -Pr 2,6-Di-F-Ph A 030 C- i -Pr CH CH L1 O H 3,5-Di-Cl-Ph A 027 CH CH CH L1 O

3,5-Di-Cl-Ph A 098 CH CH C(3,5-Di-F-Ph) L1 S Prop-1-en-2-yl H A 100 CH CH C(3,5-Di-F-Ph) L1 S -N(CH ₃ ) ₂ H A 099 CH CH C(3,5-Di-F-Ph) L1 S i -Pr H A 28 CH CH CH L1 O i -Pr 3,5-Di-Cl-Ph F 92 CH CH CH L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 83 CH CH CH L1 S -N(CH ₃ ) ₂ 3,5-Di-F-Ph A 239-INT-1 N N CH L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 239 N N CH L1 S i -Pr 3,5-Di-F-Ph A 117 N CH N L1 S -N(CH ₃ ) ₂ 3,5-Di-F-Ph A 226-3 N CH CH L1 S -N(CH ₃ ) ₂ -C(O)CH ₃ A 259-4 N CH CH L1 S -C(O)CH ₃ 3,5-Di-Cl-Ph B 221 N CH CH L1 S i -Pr -CH(CH ₃ )CH ₂ -CH(CH ₃ ) ₂ A 319 N CH CF L2 S i -Pr 3,5-Di-Cl-Ph A 309 N CH CF L1 S i -Pr 3,5-Di-Cl-Ph A 115-INT-3 N CH N L1 S Br 3,5-Di-F-Ph A 237 N C-CF ₃ N L1 S i -Pr 3,5-Di-F-Ph A 225-0 N CH CH L1 S -N(CH ₃ ) ₂

A 226 N CH CH L1 S -N(CH ₃ ) ₂ -CH(CH ₃ )CH ₂ -CH(CH ₃ ) ₂ A 240 N CH CH L1 S i -Pr

A 241 N CH CH L1 S i -Pr

A 216 N CH CH L1 S

A 208 N CH CH L1 S i -Pr 2-Cl-6-F-Ph A 230 N CH CH L1 S -N(CH ₃ ) ₂

A 232 N CH CH L1 S i -Pr

A 228 N CH CH L1 S -N(CH ₃ ) ₂

A 250 N CH CH L1 S i -Pr

A 219 CH N CH L1 S i -Pr

A 262 N CH CH L1 S i -Pr 3,5-Di-F-Ph G 249 N CH CH L1 S i -Pr

A 247 N CH CH L1 S i -Pr

A 237 N C-CF ₃ N L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 251 N CH CH L1 S i -Pr 3,5-Di-F-Ph H 215 N C-CF ₃ CH L1 S i -Pr 3,5-Di-Cl-Ph A 231 N CH CH L1 S i -Pr

A 225 N CH CH L1 S -N(CH ₃ ) ₂

A 253-0 N CH CH L1 S i -Pr 3,5-Di-F-Ph I 245 N CH CH L1 S i -Pr

A 214 N CH CH L1 S i -Pr

A 211-0 N CH CH L1 S i -Pr 3-Cl-5-(3,5-bis-Cl-Ph)-Ph A 248 N CH CH L1 S i -Pr

A 118 N CH N L1 S

3,5-Di-F-Ph A 202 N CH CH L1 S i -Pr 4-F-Ph A 242 N CH CH L1 S i -Pr

A 261 N CH CH L1 S i -Pr 3,5-Di-F-Ph K 217 N CH CH L1 S

A 227 N CH CH L1 S -N(CH ₃ ) ₂

A 124 CH CH N L1 S i -Pr 3,5-Di-F-Ph A 123 CH CH N L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A

For the avoidance of doubt, each of the compounds provided in Table 5 has been prepared and tested.

Stereoisomers and polymorphic forms Those familiar with this technology should understand that compounds can exist and be separated in optically active and racemic forms. Compounds with one or more opposing centers (including the opposing center at the sulfur atom) can be in the form of single enantiomers or diastereomers or in the form of enantiomers and/or diastereomers Exist as a mixture of enantiomers. For example, it is well known in the art that sulfenite compounds can be optically active and can exist as single enantiomers or racemic mixtures. In addition, the compounds of this specification may include one or more opposing centers, which produce a theoretical number of optically active isomers. In the current situation, the compound of formula (I) includes at least one opposing center, that is, contains the variable R¹⁰ The carbon atom. When the compound in this specification includes n opposing centers, the compound may include at most 2ⁿ Species of optical isomers. Therefore, the compounds of the present invention include at least two enantiomers covered by the present invention. This specification covers specific enantiomers or diastereomers of each compound having the applicable characteristics described herein and mixtures of different enantiomers and/or diastereomers of the compound. The optically active form can be resolved by, for example, the racemic form using selective crystallization techniques, by synthesis from optically active precursors, by opposing synthesis, by chromatographic separation using opposable stationary phases, or by enzymes Promote analysis to prepare.

The compounds may also exist in different solid forms (such as different crystalline forms) or in amorphous solid forms. This specification includes different crystalline and amorphous forms of the compound.

In addition, compounds can exist in the form of hydrates or solvates, where a certain stoichiometry of water or solvent is related to the molecule in the crystalline form. The hydrates and solvates of the compounds are also the subject of this specification.

salt In addition to neutral compounds, the salt forms of the compounds also have activity against endoparasites. The term "veterinarily acceptable salt" is used throughout the specification to describe any salt of a compound that is acceptable for administration for veterinary applications and provides the active compound after administration.

Where the compound has sufficient basicity or acidity to form a stable non-toxic acid or base salt, the compound may be in the form of a veterinary or agriculturally acceptable salt. Veterinary acceptable salts include those derived from veterinary or agriculturally acceptable inorganic or organic bases and acids. Suitable salts include those containing alkali metals (such as lithium, sodium or potassium) and alkaline earth metals (such as calcium, magnesium and barium). Salts containing transition metals (including but not limited to manganese, copper, zinc, and iron) are also suitable. In addition, this specification encompasses salts containing ammonium cations (NH ₄ ⁺ ) and substituted ammonium cations in which one or more of the hydrogen atoms are replaced by alkyl or aryl groups.

Salts derived from inorganic acids are particularly suitable, including, but not limited to, hydrohalic acids (HCl, HBr, HF, HI), sulfuric acid, nitric acid, phosphoric acid, and the like. Suitable inorganic salts also include, but are not limited to, bicarbonate and carbonate. In some embodiments, examples of veterinary and agriculturally acceptable salts are organic acid addition salts formed with organic acids, including (but not limited to) maleates, dimaleates , Fumarate, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketopentan Diacid salt and α-glycerophosphate. Of course, other acceptable organic acids can be used.

The alkali metal (such as sodium, potassium, or lithium) or alkaline earth metal (such as calcium) salt of the compound can also be prepared by reacting a sufficiently acidic residue on the compound with an alkali metal or alkaline earth metal hydroxide.

Veterinary acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound (such as an amine) with a suitable acidic functional group present in the compound, or by making a suitable acid React with suitable basic functional groups on the compounds of this specification.

流程 2

流程 3

流程 4

Process for preparing compounds The compound of formula (I) or its pharmaceutically or veterinarily acceptable salt can be prepared by using one of the following procedures 1 to 4 or procedures 5 to 12 and the procedures in the examples:Process 1

Process 2

Process 3

Process 4

Adjusting these processes to synthesize the specific compound of the present invention is within the technical level of those who are familiar with the art. In addition, the starting materials are readily available or can be prepared via known procedures.

Veterinary composition The compound and the composition containing the compound are suitable for preventing and treating parasitic infestation/infection in animals. The composition of the present specification includes an effective amount of a compound or a veterinarily acceptable salt in combination with a veterinarily acceptable carrier or diluent and optionally inactive excipients. The composition can be in a variety of solid and liquid forms suitable for various forms of administration or administration to animals. For example, a veterinary composition containing the compound may be suitable for oral administration, injectable administration (including subcutaneous and parenteral administration), and topical administration (for example, spot-on or drip-on dosage forms), The form of the composition for skin or subcutaneous administration. The composition is intended to be administered to animals, including but not limited to mammals, birds, and fish. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats, and other domestic animals or domestic mammals. Examples of birds include turkeys, chickens, ostriches and other domestic animals or domestic birds. The compound is particularly useful for protecting companion animals (such as dogs and cats) from endoparasites.

As discussed above, the composition of this specification can be in a form suitable for oral use (see, for example, US Patent No. 4,564,631, which is hereby incorporated by reference in its entirety), dietary supplements, dragees, lozenges, chewing Tablets, lozenges, hard or soft capsules, boluses, emulsions, aqueous or oily suspensions, aqueous or oily solutions, oral dosing compositions, dispersible powders or granules, premixes, syrups or elixirs, enteric-coated combinations Thing or paste. The composition to be used for oral use can be prepared according to any method known in the technology of manufacturing pharmaceutical compositions, and such compositions can contain one or more sweeteners, bittering agents, flavoring agents, coloring agents and preservatives, In order to provide medicinal delicate and delicious preparations.

Tablets may contain a mixture of active ingredients and pharmaceutically acceptable non-toxic excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch, gelatin or Gum Arabic; and lubricants such as magnesium stearate, stearic acid or talc. The lozenge may be uncoated, or it may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action for a longer period of time. For example, a time delay material may be used, such as glyceryl monostearate or glyceryl distearate. It can also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874 (all incorporated herein by reference in its entirety) to form osmotic therapeutic tablets for controlled release Agent.

Oral compositions include hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. The capsule may also be a soft gelatin capsule, in which the active ingredient is mixed with water or miscible solvents (such as propylene glycol, PEG, and ethanol) or with an oily medium (such as peanut oil, liquid paraffin, or olive oil).

In one embodiment, the compound may be administered in the form of a chewable lozenge composition or a soft chewable composition, such as those described in US 2013/0203692 A1, US 2010/0087492, US 2006/0222684, US 2004/0151759, US 7955632 All of these documents are incorporated herein by reference. The veterinary composition may be in the form of a soft chewable composition ("soft chewable tablet") that is palatable and acceptable to animals. In addition to the active ingredients, the soft chewable tablet of this specification may include one or more of the following components: solvent or solvent mixture, one or more fillers, one or more binders, one or more surfactants, one or more Humectants, one or more lubricants, one or more disintegrants, one or more coloring agents, one or more antimicrobial agents, one or more antioxidants, one or more pH adjusting agents, and one or more flavoring agents.

Solvents that can be used in the composition of this specification include (but are not limited to) various grades of liquid polyethylene glycol (PEG), including PEG 200, PEG 300, PEG 400 and PEG 540; propylene carbonate; propylene glycol; triglycerin Esters, including (but not limited to) caprylic acid/capric acid triglyceride, caprylic acid/capric acid/linoleic acid triglyceride (for example, MIGLYOL ^® 810 and 812), caprylic acid/capric acid/succinic acid triglyceride, propylene glycol Dicaprylate/dicaprate and the like; water, sorbitol solution, glycerol caprylate/caprate, and polyethylene glycol glyceride (eg, GELUCIRE ^® ); or a combination thereof.

Various fillers known in the art can be used in the soft chew composition of this specification. Fillers include, but are not limited to, corn starch, pregelatinized corn starch, soy protein crumbs, corn cobs and corn gluten flour, and the like. In some embodiments, a combination of two or more fillers can be used in the composition.

Binders that can be used in the composition of this specification include (but are not limited to) polyvinylpyrrolidone (such as Povidone); cross-linked polyvinylpyrrolidone (Crospovidone); Various grades of polyethylene glycol, including PEG 3350, PEG 4000, PEG 6000, PEG 8000 and even PEG 20,000, and their analogs; copolymers of vinylpyrrolidone and vinyl acetate (such as Copovidone) , Such as products sold by BASF under the trade name Kollidon ^® VA 64 and their analogs; starch, such as potato starch, tapioca starch or corn starch; molasses, corn syrup, honey, maple syrup and various types of sugar; or two or more More combinations of adhesives.

Humectants that can be used in the composition include, but are not limited to, glycerol (also referred to herein as glycerin), propylene glycol, cetyl alcohol, and glycerol monostearate and the like. Various grades of polyethylene glycol can also be used as a humectant.

Surfactants may be present in the composition to improve its solubility and absorption after ingestion. The surfactant is usually present at a concentration of about 1% to 10% (w/w), and more usually about 1% to about 5% (w/w). Examples of surfactants that can be used in the composition include, but are not limited to, glyceryl monooleate; polyoxyethylene sorbitan fatty acid esters; sorbitan esters, including sorbitan monooleate ( Span ^® 20); polyvinyl alcohol; polysorbate, including polysorbate 20 and polysorbate 80; d- α-tocopherol polyethylene glycol 1000 succinate (TPGS); sodium lauryl sulfate ; Copolymers of ethylene oxide and propylene oxide (such as poloxamer, such as LUTROL ^® F87 and its analogs); polyethylene glycol castor oil derivatives, including polyethylene glycol 35 castor oil ( Cremophor ^® EL), polyethylene glycol 40 hydrogenated castor oil (Cremophor ^® RH 40), polyethylene glycol 60 hydrogenated castor oil (Cremophor ^® RH60); propylene glycol monolaurate (LAUROGLYCOL ^® ); glycerides, including glycerides Alcohol caprylate/caprate (CAPMUL ^® MCM), PEGylated glycerides (GELUCIRE ^® ), PEG 300 caprylic/capric glycerides (Softigen ^® 767), PEG 400 caprylic/capric glycerides (Labrasol ^® ), PEG 300 glyceryl oleate (Labrafil ^® M-1944CS), PEG 300 glyceryl ^{linoleate (Labrafil ®} M-2125CS); polyethylene glycol stearate and polyethylene glycol hydroxystearate, Including polyethylene glycol 8 stearate (PEG 400 monostearate), polyethylene glycol 40 stearate (PEG 1750 monostearate), and the like.

The composition may contain other inert ingredients such as antioxidants, preservatives or pH stabilizers. These compounds are well known in composition technology. Antioxidants can be added to the composition of this specification to inhibit the degradation of the active agent. Suitable antioxidants include (but are not limited to) alpha tocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfite, n-propyl gallate, BHA (butylated hydroxy Anisole), BHT (butylated hydroxytoluene), monothioglycerol and the like.

The composition of this specification may also include one or more lubricants and/or processing aids. In some cases, lubricants/processing aids may also behave as solvents, and therefore, some of the components in the composition of the present invention herein may have dual functions. Lubricants/processing aids include (but are not limited to) polyethylene glycols of various molecular weight ranges, including PEG 3350 (Dow Chemical) and PEG 4000, corn oil, mineral oil, hydrogenated vegetable oil (STEROTEX or LUBRITAB), peanut oil and/or castor oil.

Many flavoring agents can be used in the compositions of this specification to improve the palatability of oral veterinary compositions. The preferred flavoring agents are those that are not derived from animal sources. In various embodiments, can be used derived from fruit, meat (including but not limited to pork, beef, chicken, fish, poultry and the like), plants, cheese, bacon, cheese-bacon and/or artificial flavors The flavoring component. Flavoring components are usually selected based on considerations related to the organism in which the soft chewable tablet will be ingested. For example, horses may prefer the apple flavor component, while dogs may prefer the meat flavor component. Although the flavoring components derived from non-animal sources are preferred, in some embodiments, natural flavoring agents containing beef or liver extracts can be used, such as beef stew flavoring, artificial beef powder flavoring, and roast beef flavoring. And corned beef flavoring and other flavoring agents.

In another embodiment of the present specification, the active composition can be administered via bolus, and can be administered locally or orally. The filling composition is the composition in which the liquid-containing composition of the present specification is administered or dripped onto the animal's oral cavity or throat or dripped onto the animal's skin or fur.

The composition of this specification can also be in the form of an oil-in-water or water-in-oil emulsion. The oil phase can be vegetable oil, such as olive oil or peanut oil; or mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifiers include naturally occurring phospholipids, such as soybeans; lecithin; and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and these partial esters and ethylene oxide Condensation products of alkanes, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, bittering agents, flavoring agents and/or preservatives.

In one embodiment, the composition of this specification may be in the form of a microemulsion. Microemulsions are very suitable as liquid carrier vehicles. Microemulsion is a quaternary system including water phase, oil phase, surfactant and auxiliary surfactant. These microemulsions are translucent and homogeneous liquids.

A microemulsion is composed of a stable dispersion of water-phase micro-droplets in an oil phase, or conversely, a stable dispersion of oil-phase micro-droplets in the water phase. The size of these micro-droplets can be less than 200 nm (the size of the emulsion is 1000 to 100,000 nm). The interfacial membrane can be composed of alternating surface active (SA) and co-surface active (co-SA) molecules, which allow the spontaneous formation of microemulsions by reducing the interfacial tension.

In one embodiment of the oil phase, the oil phase may be formed from mineral oil or vegetable oil, from unsaturated polyglycosylated glycerides or from triglycerides, or from a mixture of such compounds. In one embodiment of the oil phase, the oil phase may contain triglycerides; in another embodiment of the oil phase, the triglycerides are medium-chain triglycerides, such as C ₈ -C ₁₀ caprylic/capric triglycerides . In another embodiment of the oil phase, it may represent a v/v% range of about 2% to about 15% of the microemulsion; about 7% to about 10%; and about 8% to about 9% v/v.

The aqueous phase may include, for example, water or glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycol, or glycerol. In one embodiment, the glycol may be propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, or a mixture thereof. Generally speaking, the water phase will represent a ratio of about 1% to about 4% v/v in the microemulsion.

Surfactants used in microemulsions may include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, pegylated C ₈ -C ₁₀ glycerides or polyglyceryl-6 dioleate. In addition to these surfactants, auxiliary surfactants may include short-chain alcohols such as ethanol and propanol.

Some compounds are shared by the three components discussed above (ie, water phase, surfactant, and co-surfactant). However, the use of different compounds for each component of the same composition is within the technical level of practitioners. In one example of the amount of surfactant/co-surfactant, the ratio of co-surfactant to surfactant will be about 1/7 to about 1/2. In another example of the amount of co-surfactant, about 25% to about 75% v/v of surfactant and about 10% to about 55% v/v of co-surfactant will be present in the microemulsion.

Oily suspensions can be formulated by suspending the active ingredients in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oily suspensions may contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents (such as sucrose, saccharin or aspartame), bittering agents and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants (such as ascorbic acid) or other known preservatives.

Aqueous suspensions may contain a mixture of active materials and excipients suitable for making aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing agents or Humectants include naturally occurring phospholipids, such as lecithin, or condensation products of alkylene oxide and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain aliphatic alcohols, such as heptadecane Ethyloxyhexadecanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or ethylene oxide and derivatives Condensation products of partial esters from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents and/or Bittering agents, such as those described above.

Dispersible powders and granules suitable for preparing aqueous suspensions by adding water can provide a mixture of active ingredients and dispersing or wetting agents, suspending agents, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Additional excipients may also be present, such as sweetening agents, bittering agents, flavoring agents, and coloring agents.

Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such compositions may also contain a demulcent, preservative, flavoring and/or coloring agent.

In another embodiment of this specification, the composition may be in the form of a paste. Examples of embodiments in the form of pastes include, but are not limited to, those described in US Patent Nos. 6,787,342 and 7,001,889 (each of which is incorporated herein by reference). In addition to the compounds in this specification, the paste may further contain aerosol silica; viscosity modifier; carrier; optional absorbent; and optional coloring agent, stabilizer, surfactant or preservative .

In an embodiment of the composition, the composition may be a paste containing the compound of the specification, aerosol silica, viscosity modifier, absorbent, coloring agent and hydrophilic carrier. The hydrophilic carrier is Triacetin, monoglyceride, diglyceride or triglyceride.

The paste may also include viscosity modifiers. Suitable viscosity modifiers include (but are not limited to) polyethylene glycol (PEG), including (but not limited to) PEG 200, PEG 300, PEG 400, PEG 600; monoethanolamine, triethanolamine, glycerol, propylene glycol, poly Oxyethylene (20) sorbitan monooleate (polysorbate 80 or Tween 80) or poloxamer (for example, Pluronic L 81); absorbents such as magnesium carbonate, calcium carbonate , Starch, cellulose and its derivatives; and coloring agents, including (but not limited to) titanium dioxide, iron oxide or FD&C blue #1 aluminum lake.

In some embodiments, the composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension can be formulated according to known techniques using the above-mentioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used. Co-solvents such as ethanol, propylene glycol, glycerol formal or polyethylene glycol can also be used. Preservatives such as phenol or benzyl alcohol can be used.

In addition, it is conventionally possible to use sterile non-volatile oil as a solvent or suspension medium. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

By way of non-limiting examples, topical, transdermal and subcutaneous compositions can include emulsions, creams, ointments, gels, pastes, powders, shampoos, drop-on compositions, ready-to-use compositions, points Coating solutions and suspensions, dips and sprays. Topical application of the compound of the present invention or a composition containing at least one compound of the present invention as an active agent (in the form of a spot-on, spray-on or drip-on composition) may allow the composition of the present invention to be absorbed through the skin to reach a systemic content and distributed through the sebaceous glands. Or distributed on the surface of the skin, so as to achieve the content on the entire fur. When the compound is distributed through the sebaceous glands, the sebaceous glands can act as a reservoir, whereby there can be a lasting (up to several months) effect. The spot-on-dose composition is usually applied to a localized area that is not the entire animal area. In one embodiment, the position refers to between the shoulders. In another embodiment, the location may be a band, such as a band from the head to the tail of the animal.

The pouring-on composition is described in US Patent No. 6,010,710, which is incorporated herein by reference. Advantageously, the drop-on dosage composition may be oily, and generally contains a diluent or vehicle, and when the active ingredient is insoluble in the diluent, it also contains a solvent (for example, an organic solvent) for the active ingredient.

Organic solvents that can be used in this specification include (but are not limited to) acetyl tributyl citrate, fatty acid esters (such as dimethyl), diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, ethanol, Butyl diethylene glycol, dimethyl acetamide, dimethyl formamide, dimethyl sulfide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol Monomethyl ether, monomethyl acetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycol, propylene glycol, 2-pyrrolidone (for example, N-methylpyrrolidone), diethylene glycol monoethyl ether, Ethylene glycol, triacetin, C ₁ -C ₁₀ esters of carboxylic acids (such as butyl acetate or octyl acetate) and diethyl phthalate, or a mixture of at least two of these solvents.

The solvent will be used in proportion to the concentration of the active agent compound and the solubility of the active agent compound in the solvent. Will try to have the smallest possible volume. The difference between the vehicle composition and 100%.

The vehicle or diluent used in the composition may include dimethylsulfoxide (DMSO); glycol derivatives such as propylene glycol, glycol ether, polyethylene glycol, or glycerol. As vehicles or diluents, vegetable oils may also be mentioned, such as (but not limited to) soybean oil, peanut oil, castor oil, corn oil, cotton oil, olive oil, grapeseed oil, sunflower oil, etc.; mineral oils such as (but Not limited to) paraffin grease, paraffin wax, silicone, etc.; aliphatic hydrocarbon or cyclic hydrocarbon or, for example, medium chain (such as C ₈ to C ₁₂ ) triglyceride.

In another embodiment of this specification, a softening agent and/or a diffusing agent and/or a film-forming agent may be added. In one embodiment, the softening agent and/or diffusing agent and/or film-forming agent may be: (a) polyvinylpyrrolidone, polyvinyl alcohol, copolymer of vinyl acetate and vinylpyrrolidone, polyethylene glycol Alcohol, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylated sorbitan ester, lecithin, sodium carboxymethyl cellulose, polysiloxane oil, polydiorganosiloxane oil ( Such as polydimethylsiloxane (PDMS) oil), such as those oils containing silanol functional groups, or 45V2 oil, (b) anionic surfactants, such as alkali metal stearate, sodium stearate , Potassium stearate or ammonium stearate; calcium stearate, triethanolamine stearate; sodium rosinate; alkyl sulfates (such as sodium lauryl sulfate and sodium cetyl sulfate); dodecyl benzene Sodium sulfonate, sodium dioctyl sulfosuccinate; fatty acids (such as those derived from coconut oil), (c) cationic surfactants include the formula N ⁺ R'R"R"'R"", The water-soluble quaternary ammonium salt of Y ^- , where the group R is a hydrocarbyl group optionally hydroxylated, and Y ^- is a strong acid anion, such as halide, sulfate and sulfonate anions; cationic surfactants that can be used There are cetyltrimethylammonium bromide, (d) ^{an amine salt of the formula N +} HR'R"R'", where the group R is a hydrocarbon group that is optionally hydroxylated; there are eighteen cationic surfactants that can be used Alkylamine hydrochloride, (e) nonionic surfactants, such as sorbitan esters, which are optionally polyoxyethylated (for example, polysorbate 80); polyoxyethylated alkyl ethers; polyoxyethylated Oxypropylene fatty alcohols, such as polyoxypropylene-styrene ether; polyethylene glycol stearate, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids , Copolymers of ethylene oxide and propylene oxide, (f) amphoteric surfactants, substituted lauryl compounds such as betaine; or (g) a mixture of at least two of these agents.

In an embodiment of the amount of the softener, the softener used may account for about 0.1% to 50% by volume or 0.25% to 5% by volume. In another embodiment, the softener used may account for about 0.1% by volume to about 30% by volume, about 1% by volume to about 30% by volume, about 1% by volume to about 20% by volume, or about 5% by volume to about 20% by volume. % Ratio.

In another embodiment of this specification, the composition may be in the form of a ready-to-use solution as described in US Patent No. 6,395,765, which is incorporated herein by reference. In addition to the compounds in this specification, the ready-to-use solution may contain a crystallization inhibitor and an organic solvent or a mixture of organic solvents. In some embodiments, water may be included with the organic solvent.

In various embodiments of the present specification, the composition may include crystallization inhibition in an amount of about 1% to about 50% (w/v) or about 5% to about 40% (w/v) based on the total weight of the composition Agent. In other embodiments, the amount of the crystallization inhibitor in the composition of the present invention may be about 1% to about 30%, about 5% to about 20%, about 1% to about 15%, or about 1% to about 10% (w/w). The type of crystallization inhibitor used in the composition of the present invention is not limited, as long as it is used to inhibit the crystallization of the active or inactive agent from the composition. For example, in certain embodiments of this specification, if the solvent or co-solvent of the composition is sufficient to inhibit the formation of crystals over time when the composition is administered, the solvent or co-solvent of the composition can also act as a crystal Inhibitor.

Crystallization inhibitors suitable for use in this specification include (but are not limited to): (a) Polyvinylpyrrolidone, polyvinyl alcohol, copolymer of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, dimethyl Methylmethamide, dimethylacetamide, dimethylsulfide, 2-pyrrolidone, N-methylpyrrolidone, mannitol, glycerol, sorbitol or polyoxyethylated sorbitan Sugar alcohol ester; lecithin or sodium carboxymethyl cellulose; or acrylic acid derivatives, such as acrylate or methacrylate or their polymers or copolymers, polyethylene glycol (PEG) or polymers containing polyethylene glycol (B) Anionic surfactants, such as alkali metal stearates (such as sodium stearate, potassium stearate, or ammonium stearate) ; Calcium stearate or triethanolamine stearate; sodium rosinate; alkyl sulfates, including (but not limited to) sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzene sulfonate or dioctyl Sodium sulfosuccinate; or fatty acid (such as coconut oil); (c) cationic surfactant, such as the water-soluble quaternary ammonium salt of ^{formula N +} R'R''R'"R""Y ^-, Wherein the group R is the same or different hydrocarbyl groups optionally hydroxylated, and Y ^- is a strong acid anion, such as halide, sulfate and sulfonate anions; a cationic surfactant that can be used is brominated cetyl wax (D) ^{The amine salt of the formula N +} HR'R"R'", wherein the group R is the same or different hydrocarbyl groups which are optionally hydroxylated; there are ten types of cationic surfactants that can be used Octaalkylamine hydrochloride; (e) nonionic surfactants, such as optionally polyoxyethylated sorbitan esters, such as polysorbate 80, or polyoxyethylated alkyl ethers; Ethylene glycol stearate, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids or copolymers of ethylene oxide and propylene oxide; (f) Amphoteric surfactants, substituted lauryl compounds such as betaine; (g) mixtures of at least two of the compounds listed in (a) to (f) above; or (h) organic solvents or solvent mixtures, which After the composition is administered, the formation of crystalline or amorphous solids is inhibited.

In one embodiment of the crystallization inhibitor, a pair of crystallization inhibitors will be used. Such pairs include, for example, a combination of a polymeric film former and a surfactant. These reagents will be selected from the compounds mentioned above as crystallization inhibitors.

In some embodiments, the dielectric constant of the organic solvent may be between about 10 and about 35 or between about 20 and about 30. In other embodiments, the dielectric constant of the organic solvent may be between about 10 and about 40 or between about 20 and about 30. The content of this organic solvent or solvent mixture in the overall composition is not limited, and will be present in an amount sufficient to dissolve the required components at the required concentration. As discussed above, organic solvents can also act as crystallization inhibitors in the composition.

In some embodiments, the boiling point of one or more of the organic solvents may be lower than about 100°C or lower than about 80°C. In other embodiments, the boiling point of the organic solvent may be less than about 300°C, less than about 250°C, less than about 230°C, less than about 210°C, or less than about 200°C.

In some embodiments where there is a mixture of solvents (ie, solvents and co-solvents), the solvents may be present in the composition in a weight/weight (W/W) ratio of about 1/50 to about 1/1. The solvent will generally be in a ratio of about 1/30 to about 1/1, about 1/20 to about 1/1, or about 1/15 to about 1/1 by weight. Preferably, the two solvents will be present in a weight/weight ratio of about 1/15 to about 1/2. In some embodiments, at least one of the solvents present can improve the solubility of the active agent or act as a drying accelerator. In certain embodiments, at least one of the solvents will be miscible with water.

The composition may also include an antioxidant intended to inhibit oxidation in the air, and this agent may be present in a ratio of about 0.005% to about 1% (w/v), about 0.01% to about 0.1%, or about 0.01% to about 0.05%.

In one embodiment of the film-forming agent, the agent is a polymeric type, which includes (but is not limited to) various grades of polyvinylpyrrolidone, polyvinyl alcohol, and copolymers of vinyl acetate and vinylpyrrolidone.

In one embodiment of surfactants, the reagents include (but are not limited to) those made from nonionic surfactants; in another embodiment of the surfactants, the reagents are dehydrated by polyoxyethylene Sorbitol ester, and in another embodiment of the surfactant, the agent includes various grades of polysorbate, such as polysorbate 80.

In another embodiment of this specification, the film-forming agent and the surfactant may be incorporated in similar or identical amounts within the limit of the total amount of the crystallization inhibitor mentioned elsewhere.

The crystallization inhibitor inhibits the formation of crystals on the fur and improves the maintenance of the appearance of the skin or hair; in other words, although a high concentration of active material is used, there is no tendency towards adhesion or towards a sticky appearance. Substances other than those mentioned herein can be used as crystallization inhibitors in this specification. In one embodiment, the effectiveness of the crystallization inhibitor can be demonstrated by the following test: According to the test, 0.3 mL of the active agent containing 10% (w/v) in an appropriate solvent as defined above at 20°C The solution and 10% (w/v) of the compound acting as a crystallization inhibitor were placed on a glass slide for 24 hours, after which less than 10 crystals, preferably 0 crystals, were found on the glass slide with the naked eye.

In an example of antioxidants, the reagents are those known in the art, and include (but are not limited to) butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulfite , Propyl gallate, sodium thiosulfate or a mixture of at least two compounds with antioxidant properties.

The adjuvants of the composition discussed above are well known to physicians in the art and are commercially available or obtained through known techniques. These concentrated compositions are generally prepared by simply mixing the components as defined above; advantageously, the starting point is to mix the active material in the main solvent and then add other ingredients or adjuvants.

The volume of the applied composition will depend on the type and size of the animal, as well as the strength of the composition and the effectiveness of the active agent. In one embodiment, the composition may be administered to the animal in an amount of about 0.1 to about 20 ml. In other embodiments of the volume, the volume may be about 0.1 to about 10 ml, about 0.1 to about 5 ml, about 0.5 ml to about 10 ml, or about 0.3 to about 3 ml.

In another embodiment of this specification, the application of the dispensing composition according to this specification can also provide long-lasting and broad-spectrum efficacy when the solution is applied to mammals or birds. The spot-on-dose composition provides topical administration of concentrated solutions, suspensions, microemulsions or emulsions (dispensing solutions) to a point on the animal (usually a point between the two shoulders) for intermittent application.

For the dispensing composition, the carrier can be a liquid carrier vehicle as described in US Patent No. 6,426,333 (which is incorporated herein by reference). In one embodiment of the dispensing composition, The liquid carrier vehicle may comprise a solvent or solvent mixture, including (but not limited to) acetone; aliphatic alcohols such as methanol, ethanol, propanol, butanol, isopropanol, pentanol, hexanol, heptanol, octyl alcohol Alcohol, nonanol, cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol and the like; aromatic alcohols such as phenol, cresol, naphthol, benzyl alcohol and the like; acetonitrile; butyl diethylene Alcohol; organic amides, such as dimethylacetamide, dimethylformamide, monomethylacetamide, 2-pyrrolidone, N-methylpyrrolidone, vinylpyrrolidone and the like ; Propylene carbonate or ethylene carbonate; Dimethyl sulfide (DMSO); Glycol polymer or its ether, such as various grades of polyethylene glycol (PEG), various grades of polypropylene glycol, dipropylene glycol n-butyl Ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate; fatty acid esters such as diethyl or hexyl Diisobutyl diacid; or a mixture of at least two of these solvents.

The liquid carrier vehicle may optionally contain crystallization inhibitors, including (but not limited to) the crystallization inhibitors described in (a) to (h) above; or can act as both a solvent and a crystallization inhibitor (as described above) Definition) compounds; or mixtures of these crystallization inhibitors.

The spot-on-dose composition can be prepared by dissolving the active ingredient in a pharmaceutically or veterinarily acceptable vehicle. Alternatively, a spot-on-dose composition may be prepared by encapsulating the active ingredient to leave a residue of the therapeutic agent on the surface of the animal. Depending on the species of the host animal to be treated, the severity and type of infection, and the weight of the host, these compositions will vary with the weight of the therapeutic agent in the combination.

The dosage form may generally contain about 0.1 mg to about 5 g. In other embodiments, the dosage form may contain from about 0.5 mg to about 5 g of active agent. In one embodiment of the dosage form, the dosage may contain about 1 mg to about 500 mg of active agent, usually about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, About 600 mg, about 800 mg, or about 1000 mg.

In an embodiment of the present specification, the compound of formula (I) may be present in the composition at a concentration of about 0.05% to about 50% weight/weight. In other embodiments, the compound of formula (I) may be present at a concentration of about 0.1% to about 30% (w/w). In other embodiments, the compound of formula (I) may be about 0.5% to about 30% (w/w), about 1% to about 20% (w/w), or about 0.05% to about 10% (w/w) The concentration exists. In other embodiments, the compound of formula (I) may be about 10% to about 50% (w/w), about 10% to about 30% (w/w), about 10% to about 20% (w/w) The concentration exists. In yet another embodiment, the compound of formula (I) may be present at a concentration of about 1% to 10% (w/w) or about 5% to about 15% (w/w). In another embodiment of this specification, the active agent may be present in the composition at a concentration of about 0.1% to about 2% w/w. In yet another embodiment of this specification, the active agent may be present in the composition at a concentration of about 0.25% to about 1.5% w/w. In another embodiment of this specification, the active agent may be present in the composition at a concentration of about 1% w/w.

Treatment methods As discussed above, the compound of formula (I) is effective against endoparasites and can be used to treat and prevent parasitic infections in animals. In one embodiment, this specification provides a method for treating or preventing endoparasitic infections in or on an animal (such as a mammal or a bird), which comprises administering to the animal an endoparasitic effective amount of formula (I ) The compound or its veterinarily acceptable salt or the composition of this specification.

In some embodiments, the compound of formula (I) can also be effective against ectoparasites, and can be used to treat and prevent ectoparasite infestation on the surface of animals. In another embodiment, this specification provides a method for treating or preventing ectoparasite infestation on the body surface of an animal (such as a mammal or a bird), which comprises administering to the animal an ectoparasite-killing effective amount of formula (I) The compound or its veterinarily acceptable salt or the composition of this specification.

In another embodiment, this specification provides a method for treating or preventing endoparasitic infection and ectoparasitic infestation in and on the body of an animal, which comprises administering to the animal an effective amount of a compound of formula (I) and an effective A combination of at least a second active agent or a composition of a veterinarily acceptable salt thereof.

In yet another embodiment of the present specification, a method for treating or preventing parasite infestation at a place is provided, which comprises administering or applying a parasite-killing effective amount of a compound of formula (I) or its animal to the place. Medically acceptable salt. Regarding animal health applications, "location" is intended to mean the habitat, feedlot, area, material, or environment in which parasites grow or may grow, excluding the animal's body or surface.

In another embodiment, this specification provides methods and uses of compounds for controlling pests in plants and crops or for protecting wood-containing structures.

Treatable mammals include (but are not limited to) humans, cats, dogs, cows, chickens, cows, bison, deer, goats, horses, llamas, camels, pigs, sheep and yaks. In one embodiment of this specification, the mammal to be treated is a human, a cat, or a dog.

In one embodiment of the present specification, it has been found that the compound of formula (I) has superior efficacy against endoparasites, and specifically against endoparasites that are resistant to macrolide active agents. In one embodiment, the compounds and compositions of the present specification effectively control Haemonchus contortus , Ostertagia circumcincta and Trichostrongylus colubriformis in mammals or birds. ).

In another embodiment, this specification provides a method for treating parasitic infestation or infection in animals, which comprises administering to an animal in need an effective amount of the anthelmintic compound of this specification and an effective amount of invertebrate GABA A combination of receptor activators (including avermectin or milbemycin). Abamectins that can be used in combination with the compounds of this specification include (but are not limited to) abamectin, dimadectin, doramectin, emamectin, and Rimidectin, ivermectin, latiectin, lepimectin and selamectin. Milbemycins that can be used in combination with the compounds of this specification include, but are not limited to, milbemectin, milbemycin D, moxidectin, and nemadectin. It also includes the 5-oxo and 5-oxime derivatives of the abamectin and milbemycin.

In one embodiment, the compounds and compositions of the present specification can be used to treat or prevent endoparasitic infections of the following parasites: naked head tapeworm ( Anaplocephala / Anoplocephala ), hookworm, nematode, roundworm, Brugia , Bunostomum nematode (Bunostomum), Capillaria, Shepard nematode (Chabertia), Cooper nematode (Cooperia), nematodes cup (Cyathostomum), ring nematodes (Cylicocyclus), crown nematodes (Cylicodontophorus), the cup crown nematodes ( Cylicostephanus), nematodes nozzle (Craterostomum), Dictyocaulus (Dictyocaulus), nematodes ratchet lip (Dipetalonema), wells tapeworm (Dipylidium), heartworm (Dirofilaria), worm (dracunculus), Echinococcus (Echinococcus), intestinal nematodes live, Fasciola (Fasciola), filarial class (Filaroides), Li nematodes (Habronema), blood Mao nematodes (Haemonchus), the round worm (Metastrongylus), Moniezia (Moniezia), nematodes, neck Nematodirus , Nippostrongylus , Oesophagostomum , Onchocerca , Ostertagia , Oxyuris , Parascaris , and Schistosoma Schistosoma , Strongylus , Taenia, Toxoplasma , Strongyloides , Roundworm, Trichinella , Trichuris, Trichostrongylus , Triodontophorus, Uncinaria, Wuchereria and its combination.

In one of the preferred embodiments of this specification, the compounds and compositions of this specification are used to treat or prevent heartworm infections in dogs. These compounds have been found to be highly effective against heartworm microfilaria and L4 larvae. Therefore, these compounds can be used to protect animals from developing heartworm disease by killing the immature heartworms before they can develop into adults. In one embodiment, the compounds and compositions containing the compounds can be used to prevent the development of heartworm disease by killing heartworms in the immature stage that are resistant to macrolides. In another embodiment, the compounds and compositions of the present specification are used to treat or prevent infections by Heartworm Reptile and Heartworm Hongkong.

In another embodiment of the present specification, the parasites are Haematopus contortus , Oerster circulans, Trichostrongylus axei, Trichostrongylus serpentinus, Cooperia curticei (Cooperia curticei) , Nematodirus battus and its combination .

In another embodiment for treatment against endoparasites and against ectoparasites when combined with an ectoparasite-killing agent, the ectoparasites are one or more insects or spiders, including those insects or spiders of the following genera : Ctenocephalides , Rhipicephalus , Dermacentor , Ixodes , Boophilus , Amblyomma , Haemophilus Haemaphysalis , Hyalomma , Sarcoptes , Psoroptes , Otodectes , Chorioptes , Hyalomma , Hypoderma ( Damalinia ), Linognathus , Haematopinus , Solenoptes , Trichodectes and Felicola .

In another embodiment for the treatment of ectoparasites, the ectoparasites are from the following genera: Ctenocephalus, Rhipicephalus, Rhinocephalus, Ixodes, and/or Bovine ticks. The treated ectoparasites include (but are not limited to) fleas, ticks, mites, mosquitoes, flies, lice, bluebottles and combinations thereof. Specific examples include (but are not limited to) cat and dog fleas ( Ctenocephalides felis , Ctenocephalides genus and its analogues), ticks (Rhinocephalides genus, Ixodes genus, Ctenocephalides genus, Flower ticks and its analogues) and mites ( Demodex spp. , scabies, ear scabies and their analogs), lice ( cheyletiella spp. , Cheyletiella spp.) , Long palate lice and its analogues), mosquitoes ( Aedes spp. ), Culex spp. , Anopheles spp. and their analogues) and flies (black-horned flies) Genus ( Haematobia spp. ), Musca spp. , Stomoxys spp. , Dermatobia spp. , Cochliomyia spp. and the like). In another embodiment for the treatment of ectoparasites, the ectoparasites are fleas and/or ticks.

Additional examples of ectoparasites include (but are not limited to) the genus Boophilus, especially the species Boophilus microfidus (Bovine tick), Boophilus decoloratus (Decoloratus) and Bovine tick ( annulatus ); fly maggots Diseases, such as human skin flies (Berne in Brazil) and spiral flies ( Cochliomyia hominivorax ) (bloom flies); sheep myiasis, such as Lucilia sericata , Lucilia cuprina (Lucilia cuprina) (In Australia, New Zealand and South Africa it is called the bluebottle impact). Appropriate flies, that is, those flies whose adults constitute parasites, such as Haematobia irritans (horn flies); lice, such as Linognathus vitulorum , etc.; and mites, such as Sarcoptes scabiei and Sheep itch mite ( Psoroptes ovis ). The above list is not exhaustive, and other ectoparasites are known to be harmful to animals and humans in this technology. Such parasites include, for example, the migratory two-winged larvae.

In another embodiment of this specification, the compounds and compositions of this specification are suitable for controlling pests, such as insects selected from the group consisting of Blatella germanica , Heliothis virescens , potato beetle (L eptinotarsa decemlineata ), grass pavement ants ( Tetramorium caespitum ) and their combinations.

Plant parasitic nematodes include, for example, Anguina spp., Aphelenchoides spp., Belonoaimus spp., Bursaphelenchus spp. Ditylenchus dipsaci , Globodera spp., Heliocotylenchus spp., Heterodera spp., Longidorus spp., Meloidogyne spp .), Pratylenchus spp., Radopholus similis , Rotylenchus spp., Trichodorus spp., Tylenchorhynchus spp., Tylenchulus spp., Tylenchulus semipenetrans and Xiphinema spp.

In addition, in the presence or absence of other pesticides added to the composition, this specification can also be used to treat other pests, including (but not limited to) the following pests: (1) From the order of the Isopod, for example, ctenophora Oniscus asellus , Armadillidium vulgare , and Porcellio scaber ; (2) from Diplopoda, such as Blaniulus guttulatus ; (3) from Lipopoda ( Chilopoda), such as Geophilus carpophagus and Scutigera spp.; (4) From the order Symphyla, such as Scutigerella immaculata ; (5) From the order Thysanura, such as sugar coat Fish ( Lepisma saccharina ); (6) From the order Collembola, such as Onychiurus armatus ; (7) From the order Blatta, such as Blatta orientalis , American cockroach ( Periplaneta americana , Leucophaea maderae and German cockroach; (8) From the order Hymenoptera, such as Diprion spp., Hoplocampa spp. Lasius spp., Monomorium pharaonis and Vespa spp.; (9) From the order Siphonaptera, such as Xenopsylla cheopis and Ceratophyllus spp .); (10) From the order Anoplura (Phthiraptera), such as Damalinia spp., Haematopinus spp., Linognathus spp., human Pediculus spp., Trichodectes spp.; (11) From Arachnida, such as Acarus siro , Aceria sheldoni , Aceria sheldoni, Arachnida Dermatophagoides (Aculops spp.), Aculus spp., Anemone ticks, Argas spp., Bovine ticks, Brevipalpus spp., Alfalfa moss Mite ( Bryobia praetiosa ), Dermatophagoides, Dermanyssus gallinae , Eotetranychus spp., Epitrimerus pyri , Brown spider mite ( Eutetranychus spp.), Lepidoptera Eriophyes spp.), Hemitarsonemus spp., Hyalophthalmia , Ixodes, Black widow spider ( Latrodectus mactans ), Metatetranychus spp., Oligonychus spp .), Ornithodoros spp., Panonychus spp., Phyllocoptruta oleivora , Polyphagotarsonemus latus , Itchy mites, Rhizopus ticks Genus, Rhizoglyphus spp., Scabies, Scorpio maurus , Stenotarsonemus spp., Tarsonemus spp., Tetranychus spp.), Vasates lycopersici .; (12) From Bivalva, such as Dreissena spp.; (13) From Coleoptera, such as Coleoptera ( Acanthoscelides obtectus ), Adoretus spp., Agelastica alni , Agriotes spp., Amphimallon solstitialis , Anobium punctatum , Star Sky Anoplophora spp., Anthonomus spp., Anthrenus spp., Apogonia spp., Atomaria spp., Fur beetle ( Attage nus spp.), evil strip bean weevil (Bruchidius obtectus), the genus bean weevil (Bruchus spp.), such as turtles genus (Ceuthorhynchus spp.), Ji Yan weevil (Cleonus mendicus), Chest beetle genus (Conoderus spp. ), Weevil ( Cosmopolites spp.), Brown New Zealand Rib-winged Gill-horned beetle (Costelytra zealandica ), Weevil ( Curculio spp.), Poplar Dry Cryptorhynchus lapathi (Cryptorhynchus lapathi), Dermestes (Dermestes spp.) , Diabrotica spp., Epilachna spp., Faustinus cubae , Gibbium psylloides , Heteronychus arator , Xiuli Hylamorpha elegans , Hylotrupes bajulus , Hylotrupes bajulus, Hypera postica , Hypothenemus spp., Red-breasted large brown-toothed beetle (Lachnosterna consanguilus ), Potato beetle ( Leptlineatainotarsa decemline) ), Lissorhoptrus oryzophilus , Lixus spp., Lyctus spp., Meligethes aeneus , Melolontha , Melolontha, Cerambycidae (Lyctus spp.) Migdolus spp., Monochamus spp., Naupactus xanthographus , Niptus hololeucus , Oryctes rhinoceros , Oryzaephilus surinamensis ), black grape-eared weevil ( Otiorrhynchus sulcatus ), small blue and white beetle (Oxycetonia jucunda ), horseradish beetle ( Phaedon cochleariae ), leaf-eating beetle ( Phyllophaga spp.), Japanese beetle ( Popillia japonica ), elephant A ( Premnotrypes pp.), Psylliodes chrysocephala , Ptinus spp., Rhizobius ventralis , Rhizopertha dominica , Sitophilus spp., Sphenophorus spp., Sternechus spp., Symphyletes spp., Tenebrio molitor , Tribolium spp .), Trogoderma spp., Tychius spp., Xylotrechus spp., Zabrus spp.; (14) from Diptera (Diptera), such as Aedes, Anopheles, Bibio hortulanus , Calliphora erythrocephala , Ceratitis capitata , Chrysomyia spp., Chrysomyia spp. Cochliomyia spp., Cordylobia anthropophaga , Culex, Cuterebra spp., Dacus oleae , Dermatobia hominis , Drosophila spp .), Fannia spp., Gastrophilus spp., Hylemyia spp., Hyppobosca spp., Hypoderma spp., Spotted Liriomyza spp., Lucilia spp., Musca spp., Nezara spp., Oestrus spp., Oscinella frit , Pegomyia hyoscyami , Phorbia spp., Stomoxys spp., Tabanus spp., Tannia spp., European crane mosquito ( Tipula paludo sa ), Wohlfahrtia spp.; (15) From Gastropoda (Gastropoda), such as Arion spp., Biomphalaria spp., Bulinus spp.), Deroceras spp., Galba spp., Lymnaea spp., Oncomelania spp., Succinea spp.; ( 16) From the class of Helminths, such as Ancylostoma duodenale (Ancylostoma duodenale), Ancylostoma ceylanicum (Ancylostoma ceylanicum), Ancylostoma braziliensis (Ancylostoma braziliensis), Ancylostoma spp., Ascaris lubricoides ), Ascaris spp., Brugia malayi , Brugia timori , Bunostomum spp., Chabertia spp. ), Clonorchis spp., Cooperia spp., Dicrocoelium spp., Dictyocaulus filaria , Broad-segmented Schistocephalus ( Diphyllobothrium latum ), Dracunculus medinensis , Echinococcus granulosus , Echinococcus multilocularis , Enterobius vermicularis , Fasciola Faciola spp.), Haemonchus spp., Heterakis spp., Hymenolepis nana, Hymenolepis nana, Hyostrongulus spp., Roa filamentous Loa ), Nematodirus spp., Nodular Nematodes ( Oesophagostomum spp.), Opisthorchis spp. Onchocerca volvulus ), Ostertagia spp., Paragonimus spp., Schistosomen spp., Strongyloides fuelleborni , Strongyloides fuelleborni ( Strongyloides stercoralis , Strongyloides spp., Taenia saginata , Taenia solium , Trichinella spiralis , Trichinella nativa, Trichinella nativa (Trichinella britovi), South Trichinella spiralis (Trichinella nelsoni), false Trichinella spiralis (Trichinella pseudopsiralis), hair Strongyloides (Trichostrongulus spp.), Trichuris worms (Trichuris trichuria), Wuchereria worm (Wuchereria bancrofti) (17) From the order Heteroptera, such as Anasa tristis , Antestiopsis spp., Blissus spp., Calocoris spp. , Campylomma livida , Cavelerius spp., Cimex spp., Creontiades dilutus , Dasynus piperis , Cattail bug Dichelops furcatus , Diconocoris hewetti , Dysdercus spp., Euschistus spp., Eurygaster spp, Eurygaster spp. ( Heliopeltis spp.), Horcias nobilellus , Leptocorisa spp., Leptoglossus phyllopus , Lygus spp., Macropes excavatus ), Miridae ( Miridae , Oebalus spp., Pentomidae , Piesma quadrata , Piezodorus spp., Psallus seriatus , Pseudacysta persea , Rhodnius spp., Sahlbergella singularis , Scotinophora spp., Stephanitis nashi , Rice Straw Tibraca spp., Triatoma spp.; (18) From the order Homoptera, such as Acyrthosipon spp., Aeneolamia spp., Agonoscena spp., Aleurodes spp., Aleurolobus barodensis , Aleurothrixus spp., Amrasca spp. , Anuraphis cardui , Aonidiella spp., Aphanostigma piri , Aphis spp., Arboridia apicalis , Aonidiella spp. ( Aspidiella spp.), Buckler scale ( Aspidiotus spp.), Alder ( Atanus spp.), Potato long-whisker (Aulacarthum solani ), Small whitefly ( Bemisia spp.), Plum short-tail aphid ( Brachycaudus) helichrysii , Brachycolus spp., Brevicoryne brassicae , Calligypona marginata , Red-headed leafhopper ( Carneocephala fulgida ), Sugarcane powdered horned aphid ( Ceratovacuna lanigera ), Cicadaceae ( Cercopidae ), Ceroplastes (Ceroplastes spp.), Strawberry Aphid ( Chaetosiphon fragaefolii ), Cane Yellow Snow Shield Scale (Chionaspis tega lensis ), tea green leafhopper ( Chlorita onukii ), walnut black spot aphid ( Chromaphis juglandicola ), black brown round shield scale ( Chrysomphalus ficus ), corn leafhopper ( Cicadulina mbila ), Coccomytilus halli (Coccomytilus halli ), soft scale Coccus spp., Cryptomyzus ribis , Dalbulus spp., Dialeurodes spp., Diaphorina spp., Whiteback Diaspis spp., Doralis , Drosicha spp., Dysaphis spp., Dysmicoccus spp., Empoasca spp. ), Eriosoma spp., Erythroneura spp., Euscelis bilobatus , Geococcus coffeae , Homalodisca coagulata , Hyalopterus arundinis , Icerya spp., Idiocerus spp., Idioscopus spp., Laodelphax striatellus , Lecanium spp., Lepidosaphes spp., Lipaphis erysimi , Macrosiphum spp., Mahanarva fimbriolata , Melanaphis sacchari ), Metcalfiella , Rose wheat aphid ( Metopolophium dirhodum ), Monellia costalis , Monelliopsis pecanis , Myzus spp., Lettuce aphid ( Nasonovia ribisnigri ), Black-tailed leafhopper ( Nephotettix spp.), brown rice planthopper ( Nilaparvata lugens ), Oncometopia Genus, Orthezia praelonga , Parabemisia myricae , Paratrioza spp., Parlatoria spp., Pemphigus spp. , Corn wax cicada ( Peregrinus maidis ), Phenacoccus spp., Yang flat- winged cotton aphid (Phloeomyzus passerinii ), humulus frontal aphid ( Phorodon humuli ), Phylloxera spp., cycad brown spot and shield Kuwana (Pinnaspis aspidistrae), planococcus genus (Planococcus spp.), pear-shaped raw cotton Kuwana (Protopulvinaria pyriformis), white mulberry Kuwana shield (Pseudaulacaspis pentagona), mealybugs genus (Pseudococcus spp.), psylla spp (psylla spp.), Pteromalus spp., Pyrilla , Quadraspidiotus spp., Quesada gigas , Rastrococcus spp., Rhopalosiphum spp. ), Saissetia spp., Scaphoides titanus , Schizaphis graminum , Selenaspidus articulatus , Sogata spp. ), Sogatella furcifera , Sogatodes spp., Stictocephala festina , Tenalaphara malayensis , Tinocallis caryaefoliae , Tinocallis caryaefoliae Tomaspis spp., Toxoptera spp., Trialeurodes vaporariorum , Trialeurodes vaporariorum, Trioza spp., Typhlocyba spp., Unaspis spp. , Grape Phylloxera ( Viteus vitifolii .); (19) From the order Isoptera, such as Reticulitermes spp., Odontotermes spp.; (20) From the order Lepidoptera, such as Acronicta major , Aedia leucomelas , Agrotis spp., Alabama argillacea , Anticarsia spp., Barathra brassicae , Agrotis spp. ( Bucculatrix thurberiella ), Bupalus piniarius , Cacoecia podana , Capua reticulana , Carpocapsa pomonella , Cheimatobia brumata , Grass moth Genus ( Chilo spp.), Spruce Leaf Roller Moth (Choristoneura fumiferana ), Grape Fruit Moth ( Clysia ambiguella ), Leaf Roller (Cnaphalocerus spp. ), Egyptian Drilling Moth ( Earias insulana ), Mediterranean Powder Moth (E phestia kuehniella , Euproctis chrysorrhoea , Euxoa spp., Feltia spp., Galleria mellonella , Helicoverpa spp., Helicoverpa spp. Heliothis sspp., Hofmannophila pseudospretella , Homona magnanima , Hyponomeuta padella , Laphygma spp., Lithocolletis blancardella , winter green fruit virescens (Lithophane antennata), bean white Longqie rootworm (Loxagrotis albicosta), the genus moth (Lymantria spp.), Malacosoma caterpillar (Malacosoma neustria), cabbage armyworm (Mamestra brassicae), rice Mocis repanda , Mythimna separata , Oria spp., Oulema oryzae , Panolis flammea , Pectinophora gossypiella ), citrus leafminer (Phyllocnistis citrella), Pieris genus (Pieris spp.), diamondback moth (Plutella xylostella), the genus Spodoptera (Prodenia spp.), armyworms genus (Pseudaletia spp.), soybean armyworm (Pseudoplusia includens ), corn borer ( Pyrausta nubilalis ), Spodoptera spp., Thermesia gemmatalis , Tinea pellionella , Tineola bisselliella , Quercus bisselliella ( Tortrix viridana ), Trichoplusia spp.; (21) From Orthoptera, such as Acheta domesticus , Oriental cockroach, German cockroach, Gryllotalpa spp., Madeira cockroach, Locusta spp., Melanoplus spp., American cockroach, Schistocerca gregaria .; (22) From the order Thysanoptera, such as thrips ( Baliothrips biformis ), Enneothrips flavens , Frankliniella spp., Heliothrips spp., Hercinothrips femoralis , Kakothrips spp .), Rhipiphorothrips cruentatus , Scirtothrips spp., Taeniothrips cardamoni , Thrips spp.; (23) From Protozoa, for example Eimeria spp. (Eimeria spp.).

In each aspect of this specification, the compounds and compositions of this specification can be applied against a single pest or a combination thereof.

versus Mixture of other active agents In another embodiment, the composition containing the compound of formula (I) may also include other veterinary therapeutic agents. The veterinary medicinal agents that can be included in the composition of this specification are well known in the art (see, for example,Plumb' Veterinary Drug Handbook , 5th edition, edited by Donald C. Plumb, Blackwell Publishing, (2005) orThe Merck Veterinary Manual , 9th edition, (January 2005)), and includes (but is not limited to) acarbose, acepromazine maleate, acetaminophen, acetaminophen Azoamine, acetazolamine sodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, salbutamol sulfate (albuterol sulfate), alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, Aminocaproic acid, amidopentamide bisulfate, aminophylline/theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, molybdic acid Ammonium, amoxicillin, potassium clavulanate, deoxycholic acid amphotericin B, lipid-based amphotericin B, ampicillin, amprolium, antacid (oral), anti Snake toxin, apomorphione, apramycin sulfate, ascorbic acid, aspartame, aspirin, atenolol, atipamezole, benzene Atracurium besylate, atropine sulfate, aurnofin, aurothioglucose, azaperone, azathioprine, azithromycin azithromycin, baclofen, barbituates, benazepril, betamethasone, methacholine amine chloride, bisacodyl, Bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate, bromide, bromocriptine mesylate, budenoside ), Buprenorphine, Buspirone, Busulfan, Butorphanol Tartrate, Carmer Cabergoline, salmon calcitonin, calcitrol, calcium salt, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin (carboplatin), carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon ), cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, Ceftiofur sodium, ceftiofur, ceftiaxone sodium, cephalexin, cephalosporins, cephapirin, charcoal (activated carbon) , Chlorambucil, chloramphenicol, chlorodiazepoxide, chlorodiazepoxide +/-clidinium bromide, chlorothiazide, maleic Chlorpheniramine maleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine, cyproterone Ciprofloxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, gram Clindamycin, clofazimine, clomipramine, claonazepam, clonidine, cloprostenol sodium, clozapine Dipotassium, clorsulon, cloxacillin, codeine phosphate (codeine phosphate), colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, Dacarbazine, actinomycin d/actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, dicoquine Decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, deoxypivalate Corticosterone (desoxycorticosterone pivalate), detomidine (detomidine), dexamethasone (dexamethasone), dexpanthenol (dexpanthenol), dexraazoxane (dexraazoxane), polydextrose, diazepam (diazepam), diazoxide ( Oral), diclofenac, diclofenac sodium, dicloxacillin, diethylcarbamazine citrate, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin, digoxin, Dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaptopropanol/BAL, dimethyl sulfoxide, dinoprost tromethamine, Diphenyl alcoholamine, disopyramide phosphate, dobutamine, docusate/DSS, dolasetron mesylate, domperidone, dopamine, dolac Tine, doxapram, doxepin, doxorubicin, doxycycline, calcium disodium edetate, calcium EDTA, edrophonium chloride , Enalapril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin (e poetin) / erythropoietin, elimectin, epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynic acid )/Etanide sodium, ethanol (alcohol), etidronate sodium, etodolac, etomidate, pentobarbital-containing euthanasia, method Famotidine, fatty acids (essential fatty acids/omega fatty acids), felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride , Fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone ), flunixin meglumine (flunixin meglumine), fluorouracil (5-FU), fluoxetine (fluoxetine), fluticasone propionate (fluticasone propionate), fluvoxamine maleate (fluvoxamine maleate), a Pyrazole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide glipizide), glucagon, glucocorticoids, glucosamine/chondroitin sulfate, glutamic acid, glyburide, glycerol (oral), glycopyrrolate, gonarelin (gonadorelin), grisseofulvin, guaifenesin, halothane, polyglutaraldehyde hemoglobin-200 (OXYGLOBIN®), heparin, hydroxyethyl starch, sodium hyaluronate, hydrazine Oxazine, hydrochlorothiazide, hydrocodone bitartrate, hydrocorticosterone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate ), imithiamycin-cilastatin sodium (impenem-cilastatin sodium), imipramine (imip ramine), inamrinone lactate, insulin, interferon alpha-2a (human recombinant), iodide (sodium iodide/potassium iodide), imitate (syrup), sodium iodoposide, iron dextran, isofluoride Ether, isoproterenol, isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin/pectin, ketamine, ketoconazole, ketone Ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levamisole, levetiracetam, levothyroxine sodium, lidocaine ( lidocaine), lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine , Magnesium, mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic acid, medetomidine, medium chain three Glycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxican, melphalan, meperidine ), mercaptopurine, meropenem, metformin, methadone, methazolamide, mandelic acid/methenamine mandelate/hippurate, methimazole, metformin Thiamine, methocarbamol, methohexital sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylphenidate Methylprednisolone, metoclopramide, metoprolol, metronidoxole, mexiletine, mibolerlone, midazole Midazolam milbemycin oxime, Mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, Naloxone, mandrolone decanoate, naproxen, narcotic (opiate) analgesics, neomycin sulfate, neostigmine , Niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine ), novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, omeprazole, ondansetron, Opioid antidiarrheal drugs, orbifloxacin, oxacillin sodium, oxazepam, oxibutynin chloride, oxymorphone, oxymorphone oxytretracycline, oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide, paromomycin sulfate, parozetine, penicillamine , General information Penicillin, penicillin G, penicillin V potassium, pentazocine, pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline, pergolide mesylate (pergolide mesylate), phenobarbital, phenoxybenzamine, pheylbutazone, phenylephrine, phenylpropanolamine, phenytoin sodium, pheromones ), parenteral phosphate, phytomenadione / Vitamin K-1, pimobendan (pimobendan), piperazine, pirlimycin (pirlimycin), piroxicam (piroxicam), polyglucosaminoglycan sulfate, ponazuril (ponazuril), chlorinated Potassium, pralidoxime chloride, prazosin, prednisolone/prednisone, primidone, procainamide, procarba Hydrazine, prochlorperazine, propantheline bromide, Propionibacterium acnes injection, propofol, propranolol, protamine sulfate ), pseudoephedrine, psyllium hydrophilic mucilloid, pyridostigmine bromide, pyrilamine maleate, pyrimethamine ( pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosylmethionine (SAMe), salt/hypertonic acid Laxatives, selamectin, selegiline/l-deprenyl hydrochloride, sertraline, sevelamer, sevoflurane (sevoflurane), silymarin/milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium antimony gluconate, sodium sulfate, sodium thiosulfate, somatotropin, sota Sotalol, spectinomycin, spironolactone, stanozolol, streptococcal kinase, streptozocin, succimer, succinylcholine chloride, sulfur Sucralfate, sufentanil citrate, sulfachloropyridazine sodium, sulfadiazine/trimethoprim (trimethroprim), sulfamethoxazole/trimethoprim, Sulfadimentoxine, Sulfamethoxazine/Ometoprim (ormetoprim), sulfasalazine, taurine, tepoxaline, terbinafline, terbutaline sulfate, testosterone, Tetracycline, thiamine sodium, thiamine, thioguanine, thiopental sodium, thiotepa, thyroxine, tiamulin, ticarcillin two Sodium (ticarcilin disodium), tiletamine/zolazepam, tilmocsin, tiopronin, tobramycin sulfate, tucainide ( tocainide), tolazoline, telfenamic acid, topiramate, tramadol, triamcinolone acetonide, trientine, trilosteine trilostane), trimepraxine tartrate, tripelennamine, tylosin, urdosiol, valproic acid, vanadium, vancomycin ( vancomycin, vasopressin, vecuronium bromide, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarin sodium (warfarin sodium), xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate/zinc sulfate, zonisamide ) And mixtures thereof.

In one embodiment of this specification, arylpyrazole compounds such as phenylpyrazole may be included in the veterinary composition of this specification. Arylpyrazoles are known in the art and may be suitable for combination with the compound of formula (I) in the composition of this specification. Examples of such arylpyrazole compounds include (but are not limited to) U.S. Patent Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954; 6,998,131 and 7,759,381 (which All of these compounds described in this article are incorporated by reference). A particularly preferred arylpyrazole active agent is fipronil.

In another embodiment of the present specification, one or more of macrolides, insect repellents and/or insecticides that act as acaricides can be included in the composition of the present specification in combination with the compound. For the avoidance of doubt, the term "macrolide" as used herein includes naturally occurring and synthetic or semi-synthetic abamectin and milbemycin compounds.

The macrolides that can be used in the composition of this specification include (but are not limited to) naturally occurring abamectins (for example, including those called A ₁ a, A ₁ b, A ₂ a, A ₂ b, B ₁ a , B ₁ b, B ₂ a and B ₂ b) and milbemycin compounds, semi-synthetic abamectin and milbemycin, abamectin monosaccharide compounds and abamectin glycosides Base compound. Examples of macrolide compounds that can be used in the composition include (but are not limited to) abamectin, dimabectin, doramectin, inmectin, elimectin, ivermectin, latinobacteria Su, Limpimedine, Selamectin, ML-1,694,554 and including (but not limited to) the following milbemycins: milbemycin, milbemycin D, milbemycin A ₃ , milbemycin A _4. Milbemycin oxime, moxidectin and nimoxetine. It also includes the 5-oxo and 5-oxime derivatives of the abamectin and milbemycin.

Macrolide compounds are known in the art, and can be easily obtained commercially or via synthesis techniques known in the art. Refer to widely available technical and commercial literature. For abamectin, ivermectin and abamectin, you can refer to works such as "Ivermectin and Abamectin", 1989, MH Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag., or Albers-Schönberg, etc. People (1981), "Avermectins Structure Determination", J. Am. Chem. Soc., 103, 4216-4221. For doramectin, consult "Veterinary Parasitology", Volume 49, Issue 1, July 1993, 5-15. For milbemycin, please refer to Davies HG et al., 1986, "Avermectins and Milbemycins", Nat. Prod. Rep., 3, 87-121; Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336; US Patent No. 4,134,973 and EP 0 677 054, all of which are incorporated herein by reference.

The structures of abamectin and milbemycin are closely related, for example, by sharing a complex 16-membered macrolide ring. The natural product avermectin is disclosed in U.S. Patent No. 4,310,519, and the 22,23-dihydroavermectin compound is disclosed in U.S. Patent No. 4,199,569. In particular, reference is also made to U.S. Patent Nos. 4,468,390, 5,824,653, EP 0 007 812 A1, British Patent Specification 1 390 336, EP 0 002 916 and New Zealand Patent No. 237 086. Naturally occurring milbemycin is described in U.S. Patent No. 3,950,360 and various references cited in "The Merck Index" 12th edition, edited by S. Budavari, Merck & Co., Inc. Whitehouse Station, New Jersey (1996) References. Latiomycin is described in "International Nonproprietary Names for Pharmaceutical Substances (INN)", WHO Drug Information , Volume 17, Issue 4, Pages 263-286, (2003). Semi-synthetic derivatives of these classes of compounds are well known in the art, and are described in, for example, U.S. Patent Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, and No. 4,427,663, No. 4,310,519, No. 4,199,569, No. 5,055,596, No. 4,973,711, No. 4,978,677, No. 4,920,148 and EP 0 667 054, all of which are incorporated herein by reference.

In one embodiment, the veterinary composition of the present specification contains an effective amount of Abamectin, Dimabectin, Doramectin, Inmectin, Erimectin, Ivermectin, Latinomycin, One of lipimide, selamectin, milbemycin, milbemycin D, milbemycin A ₃ , milbemycin A ₄ , milbemycin oxime, moxidectin or nimoxetine At least one, or a combination thereof. In another embodiment, the specification provides a veterinary composition comprising an effective amount of at least one of abacin, inmectin, elimectin, ivermectin, doramectin, or selamectin者, or a combination thereof. In another embodiment, the veterinary composition of the present specification includes an effective amount of at least one of ivermectin, mimectin, milbemycin oxime, or moxidectin, or a combination thereof.

In another embodiment of the present specification, a composition is provided, which comprises a combination of a compound of formula (I) and a class of acaricides or insecticides called insect growth regulators (IGR). Compounds belonging to this group are well known to physicians and represent a wide range of different chemical classes. These compounds all work by interfering with the development or growth of insect pests. Insect growth regulators are described in, for example, U.S. Patent Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022 or UK 2 140 010 and U.S. Patent Nos. 6,096,329 and 6,685,954 (all Incorporated into this article by reference).

In one embodiment, the composition of the present specification may include an IGR compound that mimics juvenile hormones in insects or modulates their juvenile hormone content. Examples of juvenile hormone mimics include azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene ), pyriproxyfen, tetrahydroazadirachtin and 4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy) Pyridazine-3(2H)-one. In another embodiment, the composition of the present specification includes a combination of a compound of formula (I) and Mesippine or Peliprofen and a pharmaceutically acceptable carrier.

In another embodiment, the composition of the present specification includes an IGR compound as a chitin synthesis inhibitor. Chitin synthesis inhibitors include chlorofluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, and leuprofen (hexaflumoron), lufenuron, tebufenozide, teflubenzuron, triflumuron, 1-(2,6-difluorobenzyl)-3-( 2-fluoro-4-(trifluoromethyl)phenylurea, 1-(2,6-difluoro-benzyl)-3-(2-fluoro-4-(1,1,2,2- Tetrafluoroethoxy)-phenylurea and 1-(2,6-difluorobenzyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

In some embodiments, the composition of the present specification may include one or more antinematode agents, including but not limited to active agents among benzimidazole, imidazothiazole, tetrahydropyrimidine, and organic phosphate compounds. In some embodiments, benzimidazoles including (but not limited to) the following may be included in the composition: thiabendazole, cambendazole, parbendazole, orbendazole Oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, ciclobendazole ( cyclobendazole), febantel, Duobaojing and its o,o -dimethyl analogues.

In other embodiments, the composition of the present specification may include imidazothiazole compounds, including (but not limited to) tetraimidazole, levamisole, and butamisole.

In still other embodiments, the composition of the present specification may include tetrahydropyrimidine active agents, including but not limited to pyrantel, oxantel, and morantel.

Suitable organophosphate active agents include (but are not limited to) coumaphos, trichlorfon, haloxon, naftalofos and dichlorvos, heptene Phosphorus (heptenophos), mevinphos, monocrotophos, TEPP and tetrachlorvinphos.

In other embodiments, the composition may include the anti-nematode compound phenothiazine; piperazine in the form of neutral compounds and various salts; diethylcarbazine; phenols, such as diiodonitrophenol; arsenic agents, such as arsenic Amine; Ethanolamine, such as phenethylammonium, thenium closylate and methyridine; Cyanine dyes, including pyrvinium chloride, pamoate Ling and dithiazanine iodide; isothiocyanates, including bitoscanate, suramin sodium, and phthalofyne; And various natural products, including (but not limited to) hygromycin B, α-santonin and kainic acid.

In other embodiments, the composition of the present specification may include an anti-fluke agent. Suitable antiflukes include (but are not limited to) miracil (miracil), such as miracil D and mirasan (mirasan); praziquantel (praziquantel), clonazepam (clonazepam) and its 3-methyl derivatives; oltipraz, Lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, Nitroxynil (nitroxynil); various bisphenol compounds known in this technology, including hexachlorophenol, thiobisdichlorophenol, thiobisdichlorophenol, sulfonium and dinitrochlorophenol; various salicylaniline compounds , Including tribromsalan, oxyclozanide, clioxanide, rafoxanide, brotianide, bromoxanide and Closantel (closantel); triclofenidazole, difenitide (diamfenetide), clorsulon (clorsulon), triclosan (hetolin) and emetine (emetine).

Anti-sticky insect compounds can also be advantageously used in the composition of this specification, including (but not limited to) various salt forms of arecoline (arecoline), bunamidine (bunamidine), niclosamide (niclosamide), nitroisocyanide Nitroscanate, paromomycin, paromomycin II, praziquantel and epsiprantel.

In still other embodiments, the composition of the present specification may include other active agents that are effective against arthropod parasites. Suitable active agents include, but are not limited to, bromocyclen, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromosulfur. Phosphorus, Bromphos-Ethyl, Trithion, Cefensone, Chlorpyrifos, Paltox, Cythioate, Diazinon, Dichlorenthion, Dichlorenthion (diemthoate), trichlorfon, ethion, famphur, fenitrothion, fenthion, fospirate, iodofenphos, marathon (malathion), dibromophos, phosalone, phosmet, phoxim, parhamidophos, ronnel, stirofos, acrylic Permethrin, Cyhalothrin, Cypermethrin, Deltamethrin, Fenvalerate, Flucythrinate, Permethrin, Phenothrin, Pyrethrin, resmethrin, benzyl benzoate, carbon disulfide, crotamiton, difluon, diphenylamine, disulfuron, isobornyl thiocyanate acetate, methopin , Monosulfiram, pirenonylbutoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, dimethyl phthalate and compounds 1,5a,6, 9,9a,9b-hexahydro-4a(4H)-dibenzofuranaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7- Methyl bridge-1H-isoindole-1,3(2H)dione (MGK-264), dipropyl-2,5-pyridine dicarboxylate (MGK-326) and 2-(octylthio) Ethanol (MGK-874).

In another embodiment, the antiparasitic agent that may be included in the veterinary composition containing the compound of formula (I) may be a biologically active peptide or protein, including (but not limited to) ester peptides other than compounds . Such antiparasitic agents include PF1022A or its analogs and emodepside. Other cyclic ester peptide compounds that can be included in the composition comprising the compound of formula (I) are the compounds described in WO 2016/187534 A1 and WO 2017/116702 A1, which are all incorporated by reference In this article. These compounds act on neuromuscular joints by stimulating presynaptic receptors belonging to the enterocrine receptor family, leading to parasite paralysis and death. In one example of the ester peptide, the ester peptide is immer depsi (see Wilson et al., Parasitology , January 2003, 126 (Part 1): 79-86).

In another embodiment, the composition of the present specification may include an active agent derived from a neonicotinoid parasiticide. Neonicotinoid analogs bind to and inhibit insect-specific nicotinic acetylcholine receptors. In one embodiment, the neonicotinoid insecticide that can be combined with the compound of formula (I) in the composition of this specification is imidacloprid. Agents of this class are described in, for example, US Patent No. 4,742,060 or EP 0 892 060 (both of which are incorporated herein by reference). In another embodiment, the composition of the present specification may include nitenpyram, another active agent of the neonicotinoid insecticide. The use of nitenpyram to control fleas is described in US Patent No. 5,750,548, which is incorporated herein by reference in its entirety.

In certain other embodiments of this specification, the compound of formula (I) that can be combined with the composition of this specification is semicarbazone, such as metaflumizone.

In another embodiment, the composition of the present specification may advantageously include one or more isoxazoline compounds known in the art. The isoxazoline active agent is highly effective against various ectoparasites, and the combination with the compound of formula (I) will expand the scope of efficacy against these parasites. Particularly suitable isoxazoline active agents that can be combined with the compound include afoxolaner (including substantially pure active enantiomers), sarolaner, fluralaner ) (Including the substantially pure active enantiomer) and lotilaner. These active agents are described in the following documents: US 7,964,204, US 2010/0254960 A1, US2011/0159107, US2012/0309620, US2012/0030841, US2010/0069247, WO 2007/125984, WO 2012/086462, US 8318757, US 8466115 , US 8618126, US 8822466, US 8383659, US 8853186, US 9221835, US 2011/0144349, US 8,053,452; US 2010/0137612, US 8410153, US 2011/152081, WO 2012/089623, WO 2012/089622, US 8,119,671; US 7,947,715; WO 2102/120135, WO 2012/107533, WO 2011/157748, US 2011/0245274, US 2011/0245239, US 2012/0232026, US 2012/0077765, US 2012/0035122, US 2011/0251247, WO 2011 /154433, WO 2011/154434, US 2012/0238517, US 2011/0166193, WO 2011/104088, WO 2011/104087, WO 2011/104089, US 2012/015946, US 2009/0143410, WO 2007/123855 A2, US 2011/0118212, US 7951828 and US 7662972, US 2010/0137372 A1, US 2010/0179194 A2, US 2011/0086886 A2, US 2011/0059988 A1, US 2010/0179195 A1, US 2015/0126523, WO 2010/003923, WO 2010/003877, WO 2010/072602, WO 2014/134236, WO 2017/147352, US 7897630 and US 7951828, all of which are incorporated herein by reference in their entirety.

In another embodiment of this specification, nodurec acid and its derivatives can be added to the composition of this specification. These compounds are used to treat or prevent infections in humans and animals and are described in, for example, US Patent Nos. 5,399,582, 5,962,499, 6,221,894, and 6,399,786, all of which are incorporated herein by reference in their entirety. The composition may include one or more of the nordrelix acid derivatives known in the art, including all stereoisomers, such as those described in the literature cited above.

In another embodiment, an aminoacetonitrile-based insect repellent (AAD) compound, such as monepantel (ZOLVIX) and its analogs, can be added to the composition of this specification. These compounds are described in, for example, US 7,084,280 by Ducray et al. (incorporated herein by reference); Sager et al., Veterinary Parasitology, 2009, 159, 49-54; Kaminsky et al., Nature Vol. 452, 2008 3. On the 13th, 176-181.

The composition of the present specification may also include arylazol-2-ylcyanoethylamino compounds, such as those described in Soll et al. U.S. Patent No. 8,088,801 (which is incorporated herein by reference) Compounds and thioamide derivatives of these compounds (as described in US Patent No. 7,964,621 of Le Hir de Fallois, which is also incorporated herein by reference). The arylazol-2-ylcyanoethylamino-based active agent that acts on endoparasites in a systemic manner can be used in combination with the compounds in the veterinary composition of this specification.

The composition of the present specification may also include paraherquamide compounds and derivatives of these compounds, including derquantel (see Ostlind et al., Research in Veterinary Science , 1990, 48, 260-61 ; And Ostlind et al., Medical and Veterinary Entomology , 1997, 11, 407-408). The compounds of the Palamid family are known classes of compounds, which include the spirodioxinoindole core with activity against certain parasites (see Tett. Lett. 1981, 22 , 135; J. Antibiotics 1990, 43 , 1380 and J. Antibiotics 1991, 44 , 492). In addition, it is also known that structurally related marcfortine (marcfortine) family compounds (such as marcfortine AC) and can be combined with the composition of this specification (see J. Chem. Soc.-Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22 , 1977). Further references to Palamid derivatives can be found in, for example, WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, WO 09/004432 and US 2010/0197624, U.S. Patent 5,703,078 and U.S. Patent 5,750,695 , All of which are incorporated into this article by reference in their entirety.

In another embodiment of this specification, the composition may include a spinosyn active agent produced by the soil actinomycete Saccharopolyspora spinosa (see, for example, Salgado VL and Sparks TC, " The Spinosyns : Chemistry, Biochemistry, Mode of Action, and Resistance ", Comprehensive Molecular Insect Science, Volume 6, Pages 137-173, 2005) or semi-synthetic spinosyn active agents. Spinosyns are usually called factors or components A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any one of these components or a combination thereof can be used in the composition of this specification. Spinosyn compounds can be a 5,6,5-tricyclic system, which is fused with 12-membered macrolides, neutral sugars (rhamnose), and amino sugars (forosamine). These and other natural spinosyn compounds (including 21-butenyl spinosyn produced by Saccharopolyspora pagona ) that can be used in the composition of this specification can be obtained by fermentation It is produced by the conventional technology known in this technology. Other spinosyn compounds that can be used in the composition of this specification are disclosed in U.S. Patent Nos. 5,496,931; No. 5,670,364; No. 5,591,606; No. 5,571,901; No. 5,202,242; No. 5,767,253; No. 5,840,861; No. 5,670,486; No. 5,631,155 and No. 6,001,981, all of which are incorporated herein by reference in their entirety. The spinosyn compound may include, but is not limited to, spinosyn A, spinosyn D, spinosad, spinetoram, or a combination thereof. Spinosad is a combination of spinosyn A and spinosyn D, and spintoran is 3'-ethoxy-5,6-dihydrospinosad J and 3'-ethoxy spinosyn L的组合。 The combination.

Generally speaking, other active agents (other than the compound of formula (I) described above) are included in the dosage unit of this specification in an amount between about 0.1 μg and about 1000 mg. Generally, the active agent can be included in an amount of about 10 μg to about 500 mg, about 10 μg to about 400 mg, about 1 mg to about 300 mg, about 10 mg to about 200 mg, or about 10 mg to about 100 mg. More generally, the other active agent will be present in the composition of this specification in an amount from about 5 mg to about 50 mg.

Depending on the effectiveness of the active agent, the concentration of another active agent in the composition of the present specification will generally be about 0.01% to about 30% (w/w). In certain embodiments of very potent active agents including (but not limited to) macrolide active agents, the concentration of the active agent will generally be about 0.01% to about 10% (w/w), about 0.01% To about 1% (w/w), about 0.01% to about 0.5% (w/w), about 0.1% to about 0.5% (w/w), or about 0.01% to about 0.1% (w/w). In other embodiments, the concentration of the active agent will generally be about 0.1% to about 2% (w/w) or about 0.1% to about 1% (w/w).

In other embodiments, the other active agent will generally be present in a higher concentration to achieve the desired effect. In some embodiments, the active agent will be at a concentration of about 1% to about 30% (w/w), about 1% to about 20% (w/w), or about 1% to about 15% (w/w) exist. In still other embodiments, the active agent will be present in the composition at a concentration of about 5% to about 20% (w/w) or about 5% to about 15% (w/w).

In various embodiments of the present specification, another active agent can be included in the composition at a dose of about 0.001 mg to about 50 mg or about 0.5 mg to about 50 mg per kilogram of animal body weight. In other embodiments, the active agent will generally be present in an amount sufficient to deliver a dose of about 0.05 mg/kg to about 30 mg/kg, about 0.1 mg/kg to about 20 mg/kg. In other embodiments, the active agent will be present in an amount sufficient to deliver a dose of about 0.1 mg to about 10 mg, about 0.1 mg to about 1 mg, or about 0.5 mg to about 50 mg per kilogram of animal body weight.

In certain embodiments of this specification, where the other active agent is a very potent compound such as macrolide or other potent compound, the active agent will provide from about 0.001 mg/kg to about 5 mg/kg. kg, about 0.001 mg/kg to about 0.1 mg/kg, or about 0.001 mg/kg to about 0.01 mg/kg in a concentration. In still other embodiments, the active agent is present in an amount sufficient to deliver a dose of about 0.01 mg to about 2 mg or about 0.1 mg to about 1 mg per kilogram of animal body weight. In still other embodiments, another active agent may be present in an amount that delivers a dose of about 1 μg to about 200 μg or about 0.1 mg to about 1 mg per kilogram of animal body weight.

In addition to the other active agents mentioned above, a combination of two or more than two active agents can be used together with the compounds of this specification in a composition for treating pests and parasites of the desired spectrum. Deciding which individual compounds can be used in the composition of the present invention to treat specific insect infections will be completely within the skill of the physician.

This specification will now be further described by the following non-limiting examples.

Example: Preparation Example The compound of formula (I) or its pharmaceutically or veterinarily acceptable salt can be prepared by using one of the following reaction schemes. The starting materials used for its preparation may be commercially available, or may be prepared by methods known to those skilled in the art and as described in the literature. It will be appreciated that the following procedures can be modified by those skilled in the art to prepare other compounds according to the present invention. For example, those skilled in the art will understand that replacing certain starting materials or using different intermediates will enable the preparation of different compounds of formula (I).

List of abbreviations : ACN Acetonitrile AIBN Azobisisobutyronitrile BINAP (2,2´-bis(diphenylphosphino)-1,1´-binaphthalene) BSA Bovine Serum Albumin BOC Third Butoxycarbonyl BOP-Cl Bis (2-side oxy-3-oxazolidinyl) phosphinyl chloride DAST Diethylaminosulfur trifluoride DCCN,N′ -Dicyclohexylcarbodiimide solution DCM Dichloromethane DEAD Diethyl azodicarboxylate DIEA Diisopropylethylamine DMFN,N -Dimethylformamide DMAP 4-(Dimethylamino)pyridine DMSO Erjiaya EDAC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride ES Electrospray EtOAc or EA ethyl acetate HATU Hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5b]pyridine 3-oxide HOBt or HOBT 1-hydroxybenzotriazole KHMDS Potassium hexamethyldisilamido, more specifically potassium bis(trimethylsilyl)amido MeOH Methanol m-CPBA m-chloroperbenzoic acid NMO N-Methylmorpholine-N-oxide o/n overnight PE Petroleum ether Pd(dtbpf)Cl2 Dichloro[1,1'-bis(di-tertiarybutylphosphino)ferrocene]palladium(II) Pd2dba3 See (Dibenzylidene Acetone) Dipalladium(0) Pd(dppf)Cl2 [1,1'-Bis(diphenylphosphino)ferrocene]Dichloropalladium(II) complex with dichloromethane TBAF Tertiary butyl ammonium fluoride TfO Triflate THF Tetrahydrofuran TLC Thin layer chromatography

The process described in Scheme 5 can be used to prepare the following compounds: 026, 027, 028, 029, 083, 090, 092, 098, 099, 100, 101, 102, 102-1, 123, 124, 125, 126, 127, 128, 129, 130, 218, 219, 302.

In some cases of certain compounds, the process in Scheme 5 can be modified according to methods known to those skilled in the art to incorporate different functional groups in the core structure. For example, the intermediate 026-E can be used to incorporate different groups ^{corresponding to the variable R 1 in the structure.} Similarly, intermediate 026-C at the position of R ³ may be used corresponding to the different variables and groups.

Process 5

1. 3-Bromo-2- (2-ethoxy-2-oxo-ethoxy) benzoic acid methyl ester of

Put methyl 3-bromo-2-hydroxybenzoate (5.0 g, 21.6 mmol, 1.0 equivalent), ethyl bromoacetate (3.6 g, 21.6 mmol, 1 equivalent), and acetone (50 mL) into a 100 mL round bottom flask. ), K ₂ CO ₃ (8.97 g, 64.9 mmol, 3.0 equivalents). The resulting solution was stirred at 60°C overnight. The reaction mixture was allowed to cool. The solid was filtered out. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/2). 7 g of methyl 3-bromo-2-(2-ethoxy-2-oxoethoxy)benzoate (crude material) was obtained as a pale yellow solid.

2. 7-Bromo-3-hydroxyphenyl benzofuran-2-carboxylic acid methyl ester Synthesis of

Put methyl 3-bromo-2-(2-ethoxy-2-oxoethoxy) benzoate (5.0 g, 15.7 mmol, 1.0 equivalent), CH ₃ OH ( 20.0 mL, 315.3 mmol), CH ₃ ONa (1.7 g, 31.5 mmol, 2.0 equivalents). The resulting solution was stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/3). 3.5 g of methyl 7-bromo-3-hydroxy-1-benzofuran-2-carboxylate (81.9%) was obtained as a white solid.

3. 7- (3,5-dichlorophenyl) - 3-hydroxy benzofuran-2-carboxylic acid methyl ester Synthesis of

酸(1.1 g，6.1 mmol，1.1當量)、Pd(dtbpf)Cl₂ (180 mg，0.28 mmol，0.05當量)、H₂ O (2.0 mL)、THF (8.0 mL)、K₃ PO₄ (2.3 g，11.0 mmol，2.0當量)。將所得溶液在室溫攪拌隔夜。濃縮所得混合物。將殘餘物施加至具有乙酸乙酯/石油醚(1/3)之矽膠管柱上。得到1 g呈白色固體狀之7-(3,5-二氯苯基)-3-羥基-1-苯并呋喃-2-甲酸甲酯(53.6%)。Put 7-bromo-3-hydroxy-1-benzofuran-2-carboxylic acid methyl ester (1.50 g, 5.53 mmol, 1.00 equivalent), 3,5 -Dichlorophenyl

Acid (1.1 g, 6.1 mmol, 1.1 equivalent), Pd(dtbpf)Cl ₂ (180 mg, 0.28 mmol, 0.05 equivalent), H ₂ O (2.0 mL), THF (8.0 mL), K ₃ PO ₄ (2.3 g , 11.0 mmol, 2.0 equivalents). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/3). 1 g of methyl 7-(3,5-dichlorophenyl)-3-hydroxy-1-benzofuran-2-carboxylate (53.6%) was obtained as a white solid.

(3,5-dichlorophenyl) 4. 7---3- (trifluoromethanesulfonyl acyl yloxy) benzofuran-2-carboxylic acid methyl ester of

Put 7-(3,5-dichlorophenyl)-3-hydroxy-1-benzofuran-2-carboxylic acid methyl ester (0.9 g , 2.67 mmol, 1.0 equivalent), TEA (0.5 g, 5.3 mmol, 2.0 equivalent), DCM (10.0 mL), and then add Tf ₂ O (0.9 g, 3.20 mmol, 1.2 equivalent) at 0°C. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 20 mL of water. The resulting solution was extracted with 2×10 mL of dichloromethane, and the organic layers were combined. The resulting mixture was washed with 1 x 10 ml brine. The mixture was dried over anhydrous sodium sulfate and concentrated. 1.1 g of methyl 7-(3,5-dichlorophenyl)-3-(trifluoromethanesulfonyloxy)-1-benzofuran-2-carboxylate (87.8%) was obtained as a yellow solid.

3- (prop-1 -en-2-yl) benzofuran-2-carboxylic acid methyl ester of - (3,5-dichlorophenyl) 5. 7-

Put 7-(3,5-dichlorophenyl)-3-(trifluoromethanesulfonyloxy)-1-benzofuran-2 into a 50 mL round bottom flask purged and maintained with an inert nitrogen atmosphere -Methyl formate (1.10 g, 2.34 mmol, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxboron㖦 (0.5 g, 2.8 mmol, 1.2 equivalents), Pd(dtbpf)Cl ₂ (76.4 mg, 0.12 mmol, 0.05 equivalents), H ₂ O (2.0 mL), THF (8.0 mL), K ₃ PO ₄ (1.0 g , 4.7 mmol, 2.0 equivalents). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/8). Obtained 400 mg of methyl 7-(3,5-dichlorophenyl)-3-(prop-1-en-2-yl)-1-benzofuran-2-carboxylate (47.2%) as a white solid .

6. 7- (3,5-dichlorophenyl) - 3-isopropylbenzofuran-2-carboxylic acid methyl ester Synthesis of

Put 7-(3,5-dichlorophenyl)-3-(prop-1-en-2-yl)-1-benzofuran-2-carboxylic acid methyl ester (390 mg , 1.1 mmol, 1.0 equivalent), PtO ₂ (37 mg, 0.16 mmol, 0.15 equivalent), EA (10 mL). _{H 2} gas (1 atm) was introduced into the above flask. The resulting solution was stirred at room temperature for 30 minutes. The solid was filtered out. The resulting mixture was concentrated. 370 mg of methyl 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylate (94.4%) were obtained as a gray solid.

7. Synthesis of 7-(3,5- Dichlorophenyl ) -3- isopropylbenzofuran -2- carboxylic acid

Put 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylic acid methyl ester (350 mg, 1.0 mmol, 1.0 equivalent) into a 25 mL round bottom flask, NaOH (385 mg, 9.6 mmol, 10.0 equivalents), THF (1.0 mL), MeOH (4.0 mL), H ₂ O (1.0 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. Adjust the pH of the solution to 4 by adding aqueous HCl solution (1 mol/L). The solid was collected by filtration. 300 mg of 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylic acid (89.2%) was obtained as a white solid.

8. (S) -N- (𠳭-4-yl) -7- (3,5-dichlorophenyl) - 3-isopropylbenzofuran-A Synthesis of Amides -2-

Put 7-(3,5-dichlorophenyl)-3-isopropyl-1-benzofuran-2-carboxylic acid (150 mg, 0.4 mmol, 1.0 equivalent), (4S )-3,4-dihydro-2H-1-benzopiperan-4-amine (76.9 mg, 0.52 mmol, 1.20 equivalents), HATU (196 mg, 0.52 mmol, 1.20 equivalents), DIEA (166.6 mg, 1.3 mmol, 3.0 equivalents), DCM (5 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The crude product was further purified by flash preparative HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, water containing 0.05% FA and CH ₃ CN (40% CH ₃ CN increase in 13 minutes To 95%); detector, UV 254 and 220 nm. Obtained 120 mg of 7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3 as a white solid -Isopropyl-1-benzofuran-2-carboxamide (58.2%). (ES, m/z ): 480 [M+H] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.88 (dd, J = 7.9, 1.2 Hz, 1H), 7.66 (d, J = 1.9 Hz, 2H), 7.51 (dd, J = 7.5, 1.2 Hz, 1H), 7.45-7.32 (m, 3H), 7.27-7.18 (m, 1H), 6.96 (td, J = 7.5, 1.2 Hz, 1H ), 6.89 (dd, J = 8.2, 1.2 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 5.48-5.31 (m, 1H), 4.47-4.19 (m, 3H), 2.51-2.33 ( m, 1H), 2.28-2.13 (m, 1H), 1.53 (dd, J = 7.1, 2.1 Hz, 6H) ppm.

The following reaction can be used for the preparation of 7- (3,5-dichlorophenyl) -3- (N- morpholinyl) benzofuran-2-carboxylate, which can be converted to the corresponding R ³ according to Scheme 5 An alternative compound with a morpholino group at the position.

Put 7-(3,5-dichlorophenyl)-3-(trifluoromethanesulfonyloxy)-1-benzofuran-2 into a 50 mL round bottom flask purged and maintained with an inert nitrogen atmosphere -Methyl formate (500.0 mg, 1.07 mmol, 1.0 equivalent), morpholine (186 mg, 2.1 mmol, 2.0 equivalent), BINAP (133 mg, 0.21 mmol, 0.20 equivalent), Pd ₂ (dba) ₃ (97.6 mg, 0.11 mmol, 0.1 equivalent), Cs ₂ CO ₃ (0.69 g, 2.13 mmol, 2.0 equivalent), toluene (10 mL). The resulting solution was stirred at 90°C overnight. The reaction mixture was cooled to room temperature. The reaction was then quenched by adding 20 mL of water. The resulting solution was extracted with 2×15 mL of ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/5). 200 mg of methyl 7-(3,5-dichlorophenyl)-3-(morpholin-4-yl)-1-benzofuran-2-carboxylate (46.2%) was obtained as a white solid.

The following compounds can be synthesized by using the following scheme 6 and the following reaction scheme: 119, 120, 122, 199, 202, 204, 205, 207, 210, 212, 212-0A, 251, 252, 253, 253-0A, 254, 256, 258, 259, 259-5, 260, 261, 262, 263, 263-8, 285, 300, 301, 309, 310, 311, 319, 336, 337, 338.

Process 6:

1. Synthesis of 4-(3,5 -difluorophenyl ) -3- fluoropyridine

酸(25.5 g，161.4 mmol，1.2當量)、Pd(dppf)Cl₂ (4.92 g，6.7 mmol，0.05當量)、K₂ CO₃ (37.2 g，269.0 mmol，2.0當量)、H₂ O (4 mL)。將所得溶液在℃攪拌2小時。將所得溶液用3×500 mL乙酸乙酯萃取，真空濃縮。將殘餘物施加至具有乙酸乙酯/石油醚(0%至30%)之矽膠管柱上。得到26 g呈白色固體狀之4-(3,5-二氟苯基)-3-氟吡啶(92.4%)。Put 3-fluoro-4-iodopyridine (30.0 g, 134.5 mmol, 1.0 equivalent), dioxane (20 mL), 3,5-fluoro-4-iodopyridine (30.0 g, 134.5 mmol, 1.0 equivalent), dioxane (20 mL), and 3,5-fluoro-4-iodopyridine (30.0 g, 134.5 mmol, 1.0 equivalent) into a 1000 mL 3-neck round-bottom flask that was purged and maintained with an inert nitrogen atmosphere. Difluorophenyl

Acid (25.5 g, 161.4 mmol, 1.2 equivalents), Pd(dppf)Cl ₂ (4.92 g, 6.7 mmol, 0.05 equivalents), K ₂ CO ₃ (37.2 g, 269.0 mmol, 2.0 equivalents), H ₂ O (4 mL ). The resulting solution was stirred at °C for 2 hours. The resulting solution was extracted with 3×500 mL ethyl acetate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (0% to 30%). 26 g of 4-(3,5-difluorophenyl)-3-fluoropyridine (92.4%) was obtained as a white solid.

2. Synthesis of 4-(3,5 -difluorophenyl ) -3- fluoropyridine 1- oxide

Put 4-(3,5-difluorophenyl)-3-fluoropyridine (26.0 g, 124.3 mmol, 1.0 equivalent), DCM (500 mL), m-CPBA (42.9 g, 248.6 mmol, 2.0 equivalent). The resulting solution was stirred at room temperature for 1 overnight. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (EA 0% to 100%) to EA/MeOH (1/2). 21 g of 4-(3,5-difluorophenyl)-3-fluoropyridin-1-ium-1-alkoxide (75.0%) was obtained as a white solid.

3. Synthesis of 4-(3,5 -difluorophenyl ) -3- fluoropicolinonitrile

Into a 1000 mL round bottom flask purged and maintained with an inert nitrogen atmosphere was placed 4-(3,5-difluorophenyl)-3-fluoropyridin-1-ium-1-alkoxide (21.0 g, 93.3 mmol, 1.0 equivalent), CH ₃ CN (500 mL), TMSCN (23.1 g, 233.2 mmol, 2.5 equivalents), TEA (19.8 g, 195.8 mmol, 2.10 equivalents). The resulting solution was stirred at 80°C overnight. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (EA 0% to 30%). 10 g of 4-(3,5-difluorophenyl)-3-fluoropyridine-2-carbonitrile (45.8%) was obtained as an off-white solid.

4. 3-amino-7- (3,5-difluorophenyl) thieno [3,2-b] pyridine-2-carboxylic acid methyl ester of

Put 4-(3,5-difluorophenyl)-3-fluoropyridine-2-carbonitrile (6.0 g, 25.6 mmol, 1.0 equivalent), CH ₃ CN (100 mL), Methyl thioglycolate (8.2 g, 76.9 mmol, 3.0 equivalents), K ₂ CO ₃ (10.6 g, 76.86 mmol, 3 equivalents). The resulting solution was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature. The reaction was then quenched by adding 200 mL of water. The solid was collected by filtration and washed with water (3×20 mL). 6 g of methyl 3-amino-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate (73.1%) were obtained as a pale yellow solid.

5. 3-Bromo-7- (3,5-difluorophenyl) thieno [3,2-b] pyridine-2-carboxylic acid methyl ester of

Put HBr (25.0 mL), CuBr (705.4 mg, 4.9 mmol, 1.0 equivalent), 3-amino-7-(3,5- Difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid methyl ester (1.5 g, 4.7 mmol, 1.0 equivalent). _{Then a solution of NaNO 2} (388 mg, 5.6 mmol, 1.2 equivalents) in H ₂ O (5 mL) was added dropwise at 0° C. with stirring. The resulting solution was stirred at 20°C for 1 overnight. The reaction was poured into 200 mL ice water. The precipitate was collected by filtration. The solid was dissolved in 100 mL DCM and washed with 3×100 mL brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. 1.5 g of methyl 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate (83.4%) was obtained as a pale yellow solid.

6. 7- (3,5-difluorophenyl) -3-vinyl-thieno [3,2-b] pyridine-2-carboxylic acid methyl ester of

Put 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid methyl ester (500 mg , 1.3 mmol, 1.0 equivalent), THF (10 mL), potassium vinyl trifluoroborate (523 mg, 3.9 mmol, 3.0 equivalent), H ₂ O (2 mL), Pd(PPh ₃ ) ₂ Cl ₂ (91.4 mg , 0.1 mmol, 0.1 equivalent), Cs ₂ CO ₃ (1.27 g, 3.9 mmol, 3.0 equivalent). The resulting solution was stirred at 80°C overnight. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (EA 0% to 30%). 350 mg of methyl 7-(3,5-difluorophenyl)-3-vinylthieno[3,2-b]pyridine-2-carboxylate (81.2%) was obtained as a yellow solid.

7. 7- (3,5-difluorophenyl) -3-acyl-thieno [3,2-b] pyridine-2-carboxylic acid methyl ester of

Add _{K 2 OsO 4 .2H 2 O (} 200.2 mg, 0.5 mmol, 0.6 equiv) was added to 100 mL round bottom flask, acetone _{(10 mL), H 2 O} (10 mL), NMO (636.4 mg, 5.4 mmol, 6.0 equivalents), NaIO ₄ (1.2 g, 5.4 mmol, 6 equivalents), 7-(3,5-difluorophenyl)-3-vinylthieno[3,2-b]pyridine-2-carboxylic acid methyl ester (300 mg, 0.90 mmol, 1.00 equivalent). The resulting solution was stirred at room temperature overnight. The resulting solution was extracted with 3×20 mL ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3×20 mL brine. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (EA 0% to 30%). 170 mg of methyl 7-(3,5-difluorophenyl)-3-methanothieno[3,2-b]pyridine-2-carboxylate (56.3%) was obtained as a yellow solid.

8. 3- (difluoromethyl) -7- (3,5-difluorophenyl) thieno [3,2-b] pyridine-2-carboxylic acid methyl ester of

Put 7-(3,5-difluorophenyl)-3-methanothieno[3,2-b]pyridine-2-carboxylic acid methyl ester (170 mg, 0.5 mmol, 1.0 equivalent), DCM (5 mL), DAST (0.5 mL, 0.001 mmol, 0.04 equivalent). The resulting solution was stirred at room temperature for 3 hours. The reaction was added dropwise to 30 mL water/ice. The resulting solution was extracted with 3×10 mL of dichloromethane, and the organic layers were combined. The resulting mixture was washed with 3 x 20 mL brine. The resulting mixture was concentrated. The residue was applied to a silicone preparative TLC with ethyl acetate/petroleum ether (1/3). 130 mg methyl 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate (71.7%) was obtained as a white solid.

9. Synthesis of 3-( difluoromethyl )-7-(3,5 -difluorophenyl ) thieno [3,2-b] pyridine -2- carboxylic acid

Put 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid methyl ester (110 mg, 0.3 mmol, 1.0 equivalent), i-PrOH (2.0 mL, 0.1 mmol), NaOH (200 mg, 5.0 mmol, 16.1 equivalent), H ₂ O (2.0 mL, 0.3 mmol). The resulting solution was stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature. The pH value of the solution was adjusted to 5 by adding aqueous HCl solution (2 mol/L). The resulting solution was extracted with 3×10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 x 10 ml brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. 100 mg of 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid (94.6%) was obtained as a white solid.

10. 3-( Difluoromethyl )-7-(3,5 -difluorophenyl )-N-[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ] Thieno [3,2-b] pyridine -2- carboxamide Synthesis

Put 3-(difluoromethyl)-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid (80 mg, 0.2 mmol , 1.0 equivalent), DMF (3 mL), (4S)-3,4-dihydro-2H-1-benzopiperan-4-amine (70 mg, 0.5 mmol, 2.0 equivalent), DIEA (91 mg, 0.7 mmol, 3.0 equivalents), HATU (133.7 mg, 0.3 mmol, 1.5 equivalents). The resulting solution was stirred at room temperature for 1 hour. The residue was applied to a C18 column with 0.05% FA-containing H ₂ O and CH ₃ CN (40% CH ₃ CN rose to 80% in 10 minutes). Obtained 82.4 mg of 3-(difluoromethyl)-7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzo Piperan-4-yl]thieno[3,2-b]pyridine-2-carboxamide (74.4%). (ES, m/z): 479 [M+H] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.88 (d, J = 4.8 Hz, 1H), 7.63 (t, J = 54.9 Hz , 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.39-7.19 (m, 5H), 7.15 (d, J = 8.0 Hz, 1H), 7.09-6.86 (m, 3H), 5.40 (q, J = 5.9 Hz, 1H), 4.39-4.22 (m, 2H), 2.43-2.24 (m, 2H) ppm.

Compounds 199-0 and 311-1 can be prepared according to the process described in Scheme 7 below and the following procedures: Scheme 7

3- acetyl-7- (3,5-difluorophenyl) thieno [3,2-b] pyridine-2-carboxylic acid ethyl ester of

Put 3-bromo-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-ethyl carboxylate (1.0 g , 2.5 mmol, 1.0 equivalent), dioxane (20 mL), tributyl(1-ethoxyvinyl)stannane (2.7 g, 7.5 mmol, 3.0 equivalent), Pd(PPh ₃ ) ₄ (290.2 mg , 0.2 mmol, 0.1 equivalent). The resulting solution was stirred at 115°C overnight. The reaction mixture was cooled to room temperature. The reaction was then quenched by adding aqueous HCl (10 mL, 2 mol/L). The resulting solution was extracted with 3×20 mL ethyl acetate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (10% to 30%). 800 mg ethyl 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylate (88.2%) was obtained as a pale yellow solid.

Synthesis of 3- acetyl -7-(3,5 -difluorophenyl ) thieno [3,2-b] pyridine -2- carboxylic acid

Put 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid ethyl ester (300 mg, 0.8 mmol, 1.0 equivalent), i-PrOH (10 mL, 0.2 mmol, 0.2 equivalent), H ₂ O (10 mL), NaOH (300 mg, 7.5 mmol, 9.0 equivalent). The resulting solution was stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature. The pH value of the solution was adjusted to 5 by adding aqueous HCl solution (2 mol/L). The resulting solution was extracted with 3×20 mL ethyl acetate. The resulting mixture was washed with 3 x 20 ml brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. 270 mg of 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid (97.6%) was obtained as a yellow oil.

3- Acetyl- 7-(3,5 -difluorophenyl )-N-[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ] thieno [3 ,2-b) Synthesis of pyridine -2- carboxamide

Put 3-acetyl-7-(3,5-difluorophenyl)thieno[3,2-b]pyridine-2-carboxylic acid (270 mg, 0.81 mmol, 1.00 equivalent) into a 25 mL round bottom flask ), DMF (5 mL), (4S)-3,4-dihydro-2H-1-benzopiperan-4-amine (242 mg, 1.62 mmol, 2.00 equivalents), DIEA (314 mg, 2.4 mmol, 3.0 equivalents), HATU (462 mg, 1.2 mmol, 1.5 equivalents). The resulting solution was stirred at room temperature for 2 hours. The residue was applied to a C18 column with 0.05% FA-containing H ₂ O and CH ₃ CN (40% CH ₃ CN rose to 90% in 10 minutes). Obtained 180 mg of 3-acetyl-7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan- as a white solid 4-yl]thieno[3,2-b]pyridine-2-carboxamide (47.8%).

7-(3,5 -Difluorophenyl )-N-[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-(2- hydroxypropane- 2 - yl) thieno [3,2-b] pyridine-2-carboxylic Amides of

Put 3-acetyl-7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H- into a 40 mL vial purged and maintained with an inert nitrogen atmosphere. 1-Benzopiperan-4-yl]thieno[3,2-b]pyridine-2-carboxamide (160 mg, 0.3 mmol, 1.0 equivalent), DCM (10 mL). _{Then AlMe 3} (0.2 mL, 1.7 mmol, 5.0 equivalents) was added dropwise at 0°C with stirring. The resulting solution was stirred at 0 to 10°C for 1 hour. The reaction was added dropwise to 20 mL of ice water. The resulting solution was extracted with 3×10 mL of dichloromethane, and the organic layers were combined. The resulting mixture was washed with 3×20 mL brine. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/2). Obtained 35.3 mg of 7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]- as a pale yellow solid 3-(2-Hydroxyprop-2-yl)thieno[3,2-b]pyridine-2-carboxamide (21.3%). (ES, m/z): 447 [M+H] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.79 (d, J = 4.8 Hz, 1H), 7.35-7.20 (m, 5H) , 7.06-6.92 (m, 2H), 6.88 (dd, J = 8.3, 1.2 Hz, 1H), 6.60 (d, J = 7.4 Hz, 1H), 6.16 (s, 1H), 5.33 (q, J = 5.5 Hz, 1H), 4.38-4.32 (m, 1H), 4.25-4.17 (m, 1H), 2.46-2.16 (m, 2H), 1.89 (d, J = 4.2 Hz, 6H) ppm.

7-(3,5 -Difluorophenyl )-N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-(2- fluoropropane- 2 - yl) thieno [3,2-b] pyridine-2-carboxylic Amides of

Put 7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3- into an 8 mL vial (2-Hydroxyprop-2-yl)thieno[3,2-b]pyridine-2-carboxamide (108 mg, 0.2 mmol, 1.0 equivalent), DCM (3 mL). Then DAST (72.5 mg, 0.4 mmol, 2.0 equivalents) was added dropwise at 0°C with stirring. The resulting solution was stirred at room temperature for 30 minutes. The reaction was then quenched by adding 3 mL of water. The resulting solution was extracted with 3×5 mL of dichloromethane, and the organic layers were combined and concentrated. The crude product was purified by preparative HPLC. Obtained 23.1 mg of 7-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3 as a yellow solid -(2-Fluoroprop-2-yl)thieno[3,2-b]pyridine-2-carboxamide (21.3%). (ES, m/z ): 483 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO- d ₆ ): δ = 9.08 (d, J = 8.2 Hz, 1H), 8.87 (d, J = 4.8 Hz, 1H), 7.66-7.46 (m, 4H), 7.28 (d, J = 7.6 Hz, 1H), 7.21-7.11 (m, 1H), 6.90 (td, J = 7.5, 1.3 Hz, 1H), 6.78 (dd, J = 8.2, 1.2 Hz, 1H), 5.24-5.13 (m, 1H), 4.29-4.17 (m, 2H), 2.24-2.03 (m, 2H), 1.98 (d, J = 9.9 Hz, 3H), 1.90 (d, J = 9.8 Hz, 3H) ppm.

Compound 030 can be prepared according to the process described in Scheme 8 below and the following procedures: Scheme 8

1. Synthesis of 7-methoxy- 1 -benzofuran -2 -carbonitrile Put o-vanillin (50.0 g, 328.6 mmol, 1.0 equivalent) and chloroacetonitrile (29.7 g, 394.3 mmol, 1.2 equivalents), K ₂ CO ₃ (49.9 g, 361.5 mmol, 1.1 equivalents), DMF (530 mL). The resulting solution was stirred in an oil bath at 150°C for 1 hour. Subsequently, K ₂ CO ₃ (49.9 g, 361.5 mmol, 1.1 equivalents) was added and stirred for 20 minutes. The reaction was then quenched by adding 530 mL of water. The resulting solution was extracted with 3×500 mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:10). 14 g of 7-methoxy-1-benzofuran-2-carbonitrile (24.6%) was obtained as a white solid.

2. Synthesis of 4- acetyl -7- hydroxy - 1 -benzofuran -2-carbonitrile

Put 7-methoxy-1-benzofuran-2-carbonitrile (14.0 g, 80.8 mmol, 1.00 equivalent), acetyl chloride (19.0 g, 242.5 mmol, 3.0 equivalent) into a 100 mL round bottom flask, DCM (300 mL). _{Then AlCl 3} (43.1 g, 323.3 mmol, 4.0 equivalents) was added in batches at 0°C. The resulting solution was stirred at room temperature for 1 overnight. The reaction was then quenched by adding 500 mL water/ice. The resulting solution was extracted with 3×400 mL ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:10). 9 g of 4-acetyl-7-methoxy-1-benzofuran-2-carbonitrile (51.7%) was obtained as a white solid.

Synthesis of 4- (prop-1 -en-2-yl) -1-benzofuran-2-carbonitrile - A 7-methoxy-3

Into a 250 mL 3-neck round bottom flask that was purged and maintained with an inert nitrogen atmosphere was placed methyltriphenylphosphonium bromide (7.9 g, 22.3 mmol, 1.2 equivalents) and THF (50 mL). Then, n- BuLi-containing hexane (12.6 mL, 31.6 mmol, 1.7 equivalents) was added dropwise at 0°C with stirring. The resulting solution was stirred at 0°C for 30 minutes. 4-Acetyl-7-methoxy-1-benzofuran-2-carbonitrile (4.0 g, 18.5 mmol, 1.0 equivalent) was added dropwise thereto under stirring at -78°C. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 50 mL of water. The resulting solution was extracted with 3×50 mL ethyl acetate. The organic phase was washed with 2 x 50 ml brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). 1.6 g of 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carbonitrile (40.3%) was obtained as a white solid.

4. 7-methoxy---4- (prop-1 -en-2-yl) -1-benzofuran-2-carboxylic acid of

Put 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carbonitrile (1.6 g, 7.5 mmol, 1.0 equivalent) into a 100 mL round bottom flask and Aqueous NaOH (10 M) (50.0 mL). The resulting solution was stirred in an oil bath at 100°C for 1.5 hours. With aqueous HCl (6 M) of the p H of the solution was adjusted to 3-4. The solid was collected by filtration. 1.4 g of 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carboxylic acid (80.3%) was obtained as a white solid.

5. 4-isopropyl-7-methoxy---1- of benzofuran-2-carboxylic acid

Put 7-methoxy-4-(prop-1-en-2-yl)-1-benzofuran-2-carboxylic acid (2.2 g, 9.4 mmol, 1.0 equivalent), EA into a 250 mL round bottom flask (50.0 mL), PtO ₂ (0.4 g, 1.8 mmol, 0.2 equivalent). _{H 2} (g) is introduced into the above flask. The resulting solution was stirred at room temperature for 2 hours. The solid was filtered out. The resulting mixture was concentrated. 2.2 g of 4-isopropyl-7-methoxy-1-benzofuran-2-carboxylic acid (99.1%) was obtained as a yellow solid.

6. Synthesis of 7- hydroxy- 4- isopropyl- 1 -benzofuran -2-carboxylic acid

Put 4-isopropyl-7-methoxy-1-benzofuran-2-carboxylic acid (500.0 mg, 2.1 mmol, 1.0 equivalent), DCM into a 250 mL round bottom flask purged and maintained with an inert nitrogen atmosphere. (50 mL). _{Then BBr 3} (10.6 mL, 10.6 mmol, 5.0 equivalents) was added dropwise at -70°C with stirring. The resulting solution was stirred at 5°C for 4 hours. The reaction was then quenched by adding NH ₄ Cl (50 mL in water). The resulting solution was extracted with 3×50 mL DCM and concentrated. 500 mg of 7-hydroxy-4-isopropyl-1-benzofuran-2-carboxylic acid (crude product) were obtained as a colorless oil.

7. N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-7- hydroxy- 4- isopropyl- 1 -benzofuran -2- methyl Synthesis of Amine

Put 7-hydroxy-4-isopropyl-1-benzofuran-2-carboxylic acid (500.00 mg, 2.270 mmol, 1.00 equivalent), (4S)-3,4-dihydro- 2H-1-benzopiperan-4-amine (508.1 mg, 3.4 mmol, 1.5 equivalents), HATU (1726.5 mg, 4.5 mmol, 2.0 equivalents), DIEA (880.3 mg, 6.8 mmol, 3.0 equivalents), DCM (20.0 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 20 mL of water. The resulting solution was extracted with 3×30 mL DCM, and the organic layer was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:5). Obtained 250 mg of N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-7-hydroxy-4-isopropyl-1-benzene as a colorless oil And furan-2-carboxamide (31.3%).

8. Trifluoromethanesulfonic acid 2-[[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ] aminomethanyl ]-4- isopropyl- 1 -benzene Synthesis of furan -7- yl ester

Put N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-7-hydroxy in a 50 mL 3-neck round-bottom flask purged and maintained with an inert nitrogen atmosphere -4-isopropyl-1-benzofuran-2-carboxamide (240.0 mg, 0.6 mmol, 1.0 equivalent), DCM (10.0 mL), TEA (138.2 mg, 1.3 mmol, 2.0 equivalent). _{Then Tf 2} O (231.2 mg, 0.8 mmol, 1.2 equivalents) was added dropwise at -70°C with stirring. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 20 mL of NH ₄ Cl (aqueous). The resulting solution was extracted with 3×20 mL of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated. Obtained 290 mg of trifluoromethanesulfonic acid 2-[[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]aminomethanyl]-4- as a colorless oil Isopropyl-1-benzofuran-7-yl ester (87.8%).

9. 7-(3,5- Dichlorophenyl ) -N -[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-4- isopropyl- 1 - synthesis of benzofuran-2-Amides of

酸(143.6 mg，0.7 mmol，1.3當量)、Pd(dtbpf)Cl₂ (37.7 mg，0.058 mmol，0.1當量)、K₃ PO₄ (245.8 mg，1.1 mmol，2.0當量)、THF (12.00 mL)及水(3.00 mL)。將所得溶液在室溫攪拌3小時。用20 mL水稀釋所得溶液。用3×20 mL乙酸乙酯萃取所得溶液，有機層經無水硫酸鈉乾燥且濃縮。藉由製備型HPLC用以下條件(Waters-2767)來純化粗產物：管柱，X-bridge RP18，5 µm，19×100 mm；移動相，含0.03%氨之水及CH₃ CN (在13分鐘內50% CH₃ CN升至80%)；偵測器，UV 254 nm。得到87 mg呈白色固體狀之7-(3,5-二氯苯基)-N -[(4S )-3,4-二氫-2H-1-苯并哌喃-4-基]-4-異丙基-1-苯并呋喃-2-甲醯胺(31.27%)。(ES, m/z)：480[M+H]⁺ ；¹ H-NMR (300 MHz, DMSO-d6)：δ = 9.08 (d,J = 8.2 Hz, 1H), 8.05-7.87 (m, 3H), 7.72 (d,J = 7.8 Hz, 1H), 7.67 (t,J = 1.9 Hz, 1H), 7.31 (d,J = 7.9 Hz, 1H), 7.28-7.14 (m, 2H), 6.96-6.87 (m, 1H), 6.86-6.79 (m, 1H), 5.28 (q,J = 6.7 Hz, 1H), 4.30 (dt,J = 6.7, 3.8 Hz, 2H), 2.25-1.97 (m, 2H), 1.35 (d,J = 6.9 Hz, 6H) ppm。 Put trifluoromethanesulfonic acid 2-[[(4 S )-3,4-dihydro-2H-1-benzopiperan-4-yl into a 50 mL round bottom flask that was purged and maintained with an inert nitrogen ]Carboxamide]-4-isopropyl-1-benzofuran-7-yl ester (280.0 mg, 0.5 mmol, 1.0 equivalent), 3,5-dichlorophenyl

Acid (143.6 mg, 0.7 mmol, 1.3 equivalents), Pd(dtbpf)Cl ₂ (37.7 mg, 0.058 mmol, 0.1 equivalents), K ₃ PO ₄ (245.8 mg, 1.1 mmol, 2.0 equivalents), THF (12.00 mL) and Water (3.00 mL). The resulting solution was stirred at room temperature for 3 hours. Dilute the resulting solution with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC with the following conditions (Waters-2767): column, X-bridge RP18, 5 µm, 19×100 mm; mobile phase, water containing 0.03% ammonia and CH ₃ CN (at 13 50% CH ₃ CN rises to 80% within minutes); detector, UV 254 nm. Obtained 87 mg of 7-(3,5-dichlorophenyl) -N -[(4 S )-3,4-dihydro-2H-1-benzopiperan-4-yl]- as a white solid 4-isopropyl-1-benzofuran-2-carboxamide (31.27%). (ES, m/z): 480[M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d6): δ = 9.08 (d, J = 8.2 Hz, 1H), 8.05-7.87 (m, 3H ), 7.72 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 1.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.28-7.14 (m, 2H), 6.96-6.87 (m, 1H), 6.86-6.79 (m, 1H), 5.28 (q, J = 6.7 Hz, 1H), 4.30 (dt, J = 6.7, 3.8 Hz, 2H), 2.25-1.97 (m, 2H), 1.35 (d, J = 6.9 Hz, 6H) ppm.

Compounds 264 and 264-0A can be prepared according to the following procedure 9 and the following detailed procedures: Procedure 9

Exemplary procedures for compounds 264 and 264-0A : 1. Synthesis of (3,5- dichlorophenyl ) acetyl chloride

Put (3,5-dichlorophenyl)acetic acid (20.00 g, 97.547 mmol, 1.0 equivalent), toluene (120.0 mL), and sulfite chloride (50.0 g, 420.3 mmol, 4.3 equivalents) into a 1 L round bottom flask ). The resulting solution was stirred at 110°C for 2 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. 19 g of (3,5-dichlorophenyl)acetoxy chloride (crude substance) was obtained as a yellow oil.

2. Synthesis of 1-bromo-3- (3,5-dichlorophenyl) propan-2-one

(3,5-dichlorophenyl) acetyl chloride (20 g, 89.4 mmol, 1.0 equivalent) and ACN (400.0 mL) were placed in a 2 L 3-neck round bottom flask that was purged and maintained with an inert nitrogen atmosphere. _{Then TMSCHN 2} (83 mL, 116.3 mmol, 2.0 equivalents, 2M) was added dropwise at 0°C with stirring. The resulting solution was stirred at 0°C for 1 hour. HBr (40.0 mL, 547.7 mmol, 6.1 equivalents, 40%) was added dropwise thereto under stirring at 0°C. The resulting solution was allowed to react for another 2 hours at room temperature with stirring. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 200 mL of ethyl acetate, and the resulting mixture was washed with 3×200 mL of water. The mixture was dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:5). 19 g of 1-bromo-3-(3,5-dichlorophenyl)propan-2-one (crude material) was obtained as a yellow oil. MS (ESI, m/z): 281 [M+H] ⁺ .

3. 4- (3,5-dichlorophenyl) - Synthesis of 3-oxo-butyronitrile

Put 1-bromo-3-(3,5-dichlorophenyl)propan-2-one (22.0 g, 78.0 mmol, 1.0 equivalent), MeOH (120.0 mL), KCN (10.0 g, 153.5 mmol, 1.9 equivalents). The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 200 mL of water. The resulting solution was extracted with 3×200 mL ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. 5 g of 4-(3,5-dichlorophenyl)-3-oxobutyronitrile (28.1%) was obtained as an off-white solid. MS (ESI, m/z): 228 [M+H] ⁺ .

4. Synthesis of 5-(3,5- dichlorophenyl )- 4- hydroxypyridine- 3 -carbonitrile

Put 4-(3,5-dichlorophenyl)-3-oxobutyronitrile (2.0 g, 8.7 mmol, 1.0 equivalent), (two Methoxymethyl)dimethylamine (5.2 g, 43.9 mmol, 5.0 equivalents). The resulting solution was stirred at 122°C for 1 hour. Then CH ₃ COONH ₄ (5.0 g, 64.9 mmol, 7.4 equivalents) and AcOH (50.0 mL) were added. The resulting solution was allowed to react for another hour at 80°C with stirring. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with MeOH/DCM (1:10). 1.6 g of 5-(3,5-dichlorophenyl)-4-hydroxypyridine-3-carbonitrile (68.8%) was obtained as a yellow solid. MS (ESI, m/z): 265 [M+H] ⁺ .

5. Synthesis of 4- chloro -5-(3,5- dichlorophenyl ) pyridine- 3 -carbonitrile

Put 5-(3,5-dichlorophenyl)-4-hydroxypyridine-3-carbonitrile (1.6 g, 6.0 mmol, 1.0 equivalent) into a 250 mL round bottom flask maintained and purged with an inert nitrogen atmosphere and POCl ₃ (20.00 mL). The resulting solution was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. 1.6 g of 4-chloro-5-(3,5-dichlorophenyl)pyridine-3-carbonitrile (93.5%) was obtained as a brown oil. MS (ESI, m/z): 283 [M+H] ⁺ .

6. Synthesis of 3-amino-7- (3,5-dichlorophenyl) thieno [3,2-c] pyridine-2-carboxylate of

Put 4-chloro-5-(3,5-dichlorophenyl)pyridine-3-carbonitrile (1.6 g, 5.6 mmol, 1.0 equivalent) into a 250 mL round bottom flask purged and maintained with an inert nitrogen atmosphere, Ethyl thioglycolate (1.0 g, 8.5 mmol, 1.5 equivalents), acetonitrile (20.0 mL), and triethylamine (2.0 g, 19.7 mmol, 3.5 equivalents). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 100 mL of ethyl acetate, and the solid was collected by filtration. 660 mg of ethyl 3-amino-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate (31.8%) were obtained as a yellow solid. MS (ESI, m/z): 367 [M+H] ⁺ .

7. 3-Bromo-7- (3,5-dichlorophenyl) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester of

Put 3-amino-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (300.0 mg, 0.8 mmol, 1.0 Equivalent), acetonitrile (10.0 mL) and HBr (10.0 mL). _{Then CuBr 2} (365.6 mg, 1.6 mmol, 2.0 equivalents) was added at 0°C. _{NaNO 2} (85.0 mg, 1.2 mmol, 1.5 equivalents) was added thereto at 0°C. The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched by adding 100 mL 1M HCl. The resulting solution was extracted with 3×200 mL ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). 400 mg of ethyl 3-bromo-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate (crude product) was obtained as a yellow solid. MS (ESI, m/z): 430 [M+H] ⁺ .

3- (1-ethoxy-vinyl) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester of - (3,5-dichlorophenyl) 8. 7-

Put 3-bromo-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (550.0 mg , 1.2 mmol, 1.0 equivalent), tributyl(1-ethoxyvinyl)stannane (1.4 g, 3.8 mmol, 3.0 equivalent), dioxane (10.0 mL) and Pd(PPh ₃ ) ₄ (148.0 mg , 0.1 mmol, 0.1 equivalent). The resulting solution was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:3). Obtained 540 mg of ethyl 7-(3,5-dichlorophenyl)-3-(1-ethoxyvinyl)thieno[3,2-c]pyridine-2-carboxylate (crude) as a yellow solid product). MS (ESI, m/z): 422 [M+H] ⁺ .

9. 3- acetyl-7- (3,5-dichlorophenyl) thieno [3,2-c] pyridine-2-carboxylic acid ethyl ester of

Put 7-(3,5-dichlorophenyl)-3-(1-ethoxyvinyl)thieno[3,2-c]pyridine-2-ethyl carboxylate ( 530.0 mg, 1.2 mmol, 1.0 equivalent), THF (6.00 mL) and HCl (0.2 mL, 12 M). The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated in vacuo. The reaction was then quenched by adding 50 mL of 2M NaHCO _{3 aqueous solution.} The resulting solution was extracted with 3×50 mL ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo. 500 mg of ethyl 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylate (crude product) were obtained in the form of a yellow solid. MS (ESI, m/z): 394 [M+H] ⁺ .

10. Synthesis of 3- acetyl -7-(3,5- dichlorophenyl ) thieno [3,2-c] pyridine -2- carboxylic acid

Put 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (500.0 mg, 1.2 mmol, 1.0 equivalent) into a 40 mL vial ), THF (5.0 mL), water (5.0 mL) and LiOH.H ₂ O (160.0 mg, 3.8 mmol, 3.0 equivalents). The resulting solution was stirred at room temperature for 1 hour. (1M) of the p H of the solution was adjusted to 3 with aqueous HCl. The resulting solution was extracted with 3×20 mL ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. 330 mg of 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid (71.0%) was obtained as a white solid. MS (ESI, m/z): 366 [M+H] ⁺ .

11. 3- Acetyl- 7-(3,5- dichlorophenyl ) -N -[(4 S )-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ] thiophene and [3,2-c] pyridine-2-carboxylic Amides of

Put 3-acetyl-7-(3,5-dichlorophenyl)thieno[3,2-c]pyridine-2-carboxylic acid (330.0 mg, 0.9 mmol, 1.0 equivalent) into a 50 mL round bottom flask ), (4 S )-3,4-dihydro-2H-1-benzopiperan-4-amine (202.0 mg, 1.3 mmol, 1.5 equivalents), DMF (3.00 mL), HATU (687.0 mg, 1.8 mmol , 2.0 equivalents), DIEA (350.0 mg, 2.7 mmol, 3.0 equivalents). The resulting solution was stirred at room temperature for 1 hour. The crude product was purified by flash preparative HPLC with the following conditions (IntelFlash-1): C ₁₈ ; mobile phase, _{increasing from CH 3} CN:H ₂ O=20% to CH ₃ CN:H ₂ O=90% within 20 minutes . Obtained 320 mg of 3-acetyl-7-(3,5-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan- as a yellow solid 4-yl]thieno[3,2-c]pyridine-2-carboxamide (71.4%). MS (ESI, m/z): 497 [M+H] ⁺ .

12. 7-(3,5- Dichlorophenyl ) -N -[(4 S )-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-(2- hydroxyl Synthesis of propan -2- yl ) thieno [3,2-c] pyridine -2- carboxamide

_{AlMe 3} (5 mL, 2M in hexane) was placed in a 50 mL round bottom flask purged and maintained with an inert nitrogen atmosphere. Then add 3-acetyl-7-(3,5-dichlorophenyl) -N -[(4 S )-3,4-dihydro-2H-1-benzopiperan-4- at 0℃ Yl]thieno[3,2-c]pyridine-2-carboxamide (140.0 mg, 0.2 mmol, 1.0 equivalent). The resulting solution was stirred at room temperature for 1 hour. With aqueous HCl (3 M) of the solution was adjusted to p H 2. The resulting solution was extracted with 3×20 mL ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Purify the crude product by flash preparative HPLC with the following conditions (IntelFlash-1): column, C ₁₈ silica gel; mobile phase, _{increase from CH 3} CN:H ₂ O=20% to CH ₃ CN:H _{2 within 20 minutes} O=50%. Obtained 5.4 mg of 7-(3,5-dichlorophenyl) -N -[(4 S )-3,4-dihydro-2H-1-benzopiperan-4-yl]- as a white solid 3-(2-Hydroxyprop-2-yl)thieno[3,2-c]pyridine-2-carboxamide (3.7%). MS (ESI, m/z): 513 [M+H] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 9.58 (s, 1H), 9.40 (d, J = 7.8 Hz, 1H), 8.45 (s, 1H), 7.71 (s, 3H), 7.20-7.13 (m, 2H), 6.90-6.86 (m,1H), 6.76 (d, J = 9.0 Hz, 1H), 5.14-5.13 (d, J = 1.8 Hz, 1H), 4.18 (s, 2H), 2.11-2.10 (m, 1H), 2.00-1.95 (m, 1H), 1.68 (s, 6H) ppm.

13. 7-(3,5- Dichlorophenyl )-N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-(2- fluoropropane Synthesis of -2- yl ) thieno [3,2-c] pyridine -2- carboxamide

Put 7-(3,5-dichlorophenyl)-N -((4 S )-3,4-dihydro-2H-1-benzene into a 50 mL round-bottomed flask that was purged and maintained with an inert nitrogen atmosphere Piperan-4-yl]-3-(2-hydroxyprop-2-yl)thieno[3,2-c]pyridine-2-carboxamide (35.0 mg, 0.06 mmol, 1.0 equivalent), DCM ( 5.0 mL), DAST (21.0 mg, 0.1 mmol, 1.9 equivalents). The resulting solution was stirred at room temperature for 30 minutes. The reaction was then quenched by adding 5 mL of water. The resulting solution was extracted with 3×5 mL of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Purify the crude product by flash preparative HPLC with the following conditions (IntelFlash-1): column, C ₁₈ silica gel; mobile phase, _{increase from CH 3} CN:H ₂ O=45% to CH ₃ CN:H _{2 within 20 minutes} O=65%. Obtained 22.7 mg of 7-(3,5-dichlorophenyl) -N -[(4 S )-3,4-dihydro-2H-1-benzopiperan-4-yl]- as a white solid 3-(2-Fluoroprop-2-yl)thieno[3,2-c]pyridine-2-carboxamide (64.6%). MS (ESI, m/z): 515 [M+H] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 9.37 (s, 1H), 8.50 (s, 1H), 7.54-7.50 (m , 3H), 7.31 (s, 1H), 7.23 (d, J = 7.4 Hz, 1H), 6.99-6.90 (m, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.31 (d, J = 7.5 Hz, 1H), 5.33-5.25 (m, 1H), 4.39-4.32 (m, 1H), 4.25-4.17 (m, 1H), 2.37-2.34 (m, 1H), 2.27-2.22 (m, 1H) , 2.07 (d, J = 7.1 Hz, 3H), 1.99 (d, J = 7.1 Hz, 3H) ppm.

The following compounds can be prepared according to Scheme 10 below and the following detailed procedures: 121, 226-3, 215, 227, 224, 225, 228, 225-0A, 230, 226, 234.

Process 10

Exemplary procedure for compound 226-3 : 1. Synthesis of 3- chloro - 4 -methoxypyridine

Put 3-chloro-4-nitropyridine (30.00 g, 189.2 mmol, 1.0 equivalent), MeOH (400.0 mL), CH ₃ ONa (56.7 mL, 5 mol/L, 1.50 equivalent) into a 1000 mL round bottom flask . The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was dissolved in 500 mL EA. The resulting mixture was washed with 3 x 500 ml brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. 25 g of 3-chloro-4-methoxypyridine (92.0%) was obtained as a yellow oil.

2. Synthesis of 3- chloro - 4 -methoxypyridine- 1 -on- 1- alkoxide

Into a 1000 mL round bottom flask was placed 3-chloro-4-methoxypyridine (25.00 g, 174.131 mmol, 1.00 equivalent), DCM (500.0 mL), m-CPBA (60.1 g, 348.2 mmol, 2.0 equivalent). The resulting solution was stirred at room temperature for 2h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (EA 0% to 100%) to EA/MeOH (1/2). 30 g of 3-chloro-4-methoxypyridin-1-ium-1-alkoxide (crude material) was obtained in the form of an off-white solid.

3. Synthesis of 3- chloro - 4 -methoxypyridine- 2 -carbonitrile

Put 3-chloro-4-methoxypyridine-1-onium-1-alkoxide (30.00 g, 188.0 mmol, 1.0 equivalent), CH ₃ CN (600.0 mL), TMSCN (46.6 g, 470.0 mmol, 2.5 equivalents), TEA (39.95 g, 394.8 mmol, 2.1 equivalents). The resulting solution was stirred at 80°C for 6 hours. The resulting mixture was concentrated in vacuo. 35 g of 3-chloro-4-methoxypyridine-2-carbonitrile (crude material) was obtained in the form of a brown solid.

4. 3-amino-7-methoxy-thieno [3,2-b] pyridine-2-carboxylic acid methyl ester of

Put 3-chloro-4-methoxypyridine-2-carbonitrile (16.00 g, 94.9 mmol, 1.0 equivalent), CH ₃ CN (300.0 mL), methyl thioglycolate ( 40.30 g, 379.6 mmol, 4.0 equivalents), K ₂ CO ₃ (52.47 g, 379.6 mmol, 4.0 equivalents). The resulting solution was stirred at 80°C for 1 overnight. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (EA 0% to 70%). 2.7 g of methyl 3-amino-7-methoxythieno[3,2-b]pyridine-2-carboxylate (11.9%) were obtained as a yellow solid.

The 3- (dimethylamino) -7-methoxy-thieno [3,2-b] pyridine-2-carboxylic acid methyl ester of

Put 3-amino-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid methyl ester (1.00 g, 4.1 mmol, 1.0 equivalent), HOAc (40.0 mL) into a 250 mL round bottom flask ), HCHO (1260.2 mg, 41.9 mmol, 10.0 equivalents), NaBH ₃ CN (2637.5 mg, 41.9 mmol, 10.0 equivalents). The resulting solution was stirred at 35°C for 3 hours. The reaction was then quenched by adding 50 mL of water. The resulting solution was extracted with 3×50 mL ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 × 100 ml NaHCO ₃ (aqueous) and 3 × 100 mL brine. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (EA 0% to 50%). 1.1 g of methyl 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylate (98.4%) was obtained as a pale yellow solid.

6. Synthesis of 3-( dimethylamino )-7- methoxythieno [3,2-b] pyridine -2- carboxylic acid

Put 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid methyl ester (130.0 mg, 0.4 mmol, 1.0 equivalent) into a 100 mL round bottom flask, THF (3.0 mL), NaOH (130.00 mg, 3.2 mmol, 6.6 equivalents), H ₂ O (3.0 mL). The resulting solution was stirred at 55°C for 3 hours. The resulting mixture was concentrated in vacuo. 150 mg of 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid (crude product) were obtained as a yellow solid.

7. N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-( dimethylamino )-7- methoxythieno [3,2 -b] Synthesis of pyridine -2- carboxamide

Put 3-(dimethylamino)-7-methoxythieno[3,2-b]pyridine-2-carboxylic acid (900.0 mg, 3.5 mmol, 1.0 equivalent), DMF ( 20.0 mL), (4S)-3,4-dihydro-2H-1-benzopiperan-4-amine (532.2 mg, 3.5 mmol, 1.0 equivalent), DIEA (1383.1 mg, 10.7 mmol, 3.0 equivalent), HATU (2034.60 mg, 5.3 mmol, 1.5 equivalents). The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched by adding 20 mL of water. The resulting solution was extracted with 3×20 mL ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 x 20 ml brine. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (0% to 50%). Obtained 530 mg of N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino)-7-methoxy as a yellow semi-solid Thieno[3,2-b]pyridine-2-carboxamide (38.7%).

8. N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-( dimethylamino )-7- hydroxythieno [3,2-b ] Synthesis of pyridine -2- carboxamide

Put N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino)-7-methoxythiophene into a 40 mL vial And [3,2-b]pyridine-2-carboxamide (500.0 mg, 1.3 mmol, 1.0 equivalent), DMF (10.0 mL, 0.014 mmol), LiCl (300.1 mg, 7.0 mmol, 5.4 equivalent). The resulting solution was stirred at 140°C for 6 hours. The reaction mixture was cooled to room temperature. The residue was applied to a _{silica C18 column with H 2} O containing 0.05% TFA and CH ₃ CN (20% CH ₃ CN rose to 60% in 12 minutes). Obtained 200 mg of N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino)-7-hydroxythiophene as a pale yellow solid And [3,2-b]pyridine-2-carboxamide (41.5%).

9. Trifluoromethanesulfonic acid 2-[[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ] aminomethanyl ]-3-( dimethylamino ) thiophene and [3,2-b] pyridin-7-yl ester the synthesis of

Put N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-( Dimethylamino)-7-hydroxythieno[3,2-b]pyridine-2-carboxamide (180.0 mg, 0.4 mmol, 1.0 equivalent), DCM (5.0 mL), TEA (493.0 mg, 4.8 mmol, 10.0 equivalents), Tf ₂ O (687.3 mg, 2.4 mmol, 5.0 equivalents). The resulting solution was stirred at 10°C for 2 hours. The reaction was then quenched by adding 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 3 x 20 mL brine. The resulting mixture was concentrated in vacuo. The residue was applied to a silicone preparative TLC with ethyl acetate/petroleum ether (1/3). 150 mg of trifluoromethanesulfonic acid 2-[[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]aminomethanyl]-3- (Dimethylamino)thieno[3,2-b]pyridin-7-yl ester (61.3%).

10. N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-( dimethylamino )-7-(1- ethoxyvinyl ) thieno [3,2-b] pyridine-2-carboxylic Amides of

Toluene (20.0 mL) and trifluoromethanesulfonic acid 2-[((4S)-3,4-dihydro-2H-1-benzopiper Pyran-4-yl]aminomethanyl]-3-(dimethylamino)thieno[3,2-b]pyridin-7-yl ester (500.0 mg, 1.0 mmol, 1.0 equivalent), tributyl ( 1-ethoxyvinyl)stannane (1 g, 2.7 mmol, 2.7 equivalents), Pd(dppf)Cl ₂ (160.00 mg, 0.2 mmol, 0.2 equivalents), K ₂ CO ₃ (250.0 mg, 1.8 mmol, 1.8 equivalent). The resulting solution was stirred at 100°C for 2 hours. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:4). Obtain 350 mg of N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino)-7-(1- Ethoxyvinyl)thieno[3,2-b]pyridine-2-carboxamide (82.8%).

11. 7- Acetyl- N-[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-( dimethylamino ) thieno [3,2 -b] Synthesis of pyridine -2- carboxamide

Put THF (5.0 mL), N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl)-3-(dimethylamino) into a 50 mL round bottom flask. )-7-(1-ethoxyvinyl)thieno[3,2-b]pyridine-2-carboxamide (350.0 mg, 0.8 mmol, 1.0 equivalent), HCl (6M) (5.0 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 10 mL of water. The resulting solution was extracted with 3×20 mL ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:3). Obtained 180 mg of 7-acetyl-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino) as a yellow solid Thieno[3,2-b]pyridine-2-carboxamide (55.0%). ¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.96 (d, J = 4.7 Hz, 1H), 8.04 (d, J = 4.8 Hz, 1H), 7.37-7.32 (m, 1H), 7.28- 7.16 (m, 1H), 6.97-6.91 (m, 1H), 6.86 (dd, J = 8.2, 1.2 Hz, 1H), 5.31 (t, J = 5.6 Hz, 1H), 4.39-4.32 (m, 1H) , 4.27-4.22 (m, 1H), 2.99 (s, 6H), 2.80 (s, 3H), 2.39-2.33 (m, 1H), 2.21-2.16 (m, 1H) ppm.

12. N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-( dimethylamino )-7-(2- hydroxy- 4 -methyl Synthesis of pent- 3 -en -2- yl ) thieno [3,2-b] pyridine -2- carboxamide

Put THF (5.0 mL), 7-acetyl-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl] into a 50 mL 3-neck round bottom flask -3-(Dimethylamino)thieno[3,2-b]pyridine-2-carboxamide (300.0 mg, 0.7 mmol, 1.0 equivalent). Then (2-methylprop-1-en-1-yl)magnesium bromide (1.0 mL, 0.006 mmol, 0.01 equivalent) was added dropwise at 0°C with stirring. The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding water/ice. The resulting solution was extracted with 3×20 mL ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:4). 150 mg of N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino)-7-(2- Hydroxy-4-methylpent-3-en-2-yl)thieno[3,2-b]pyridine-2-carboxamide (43.7%).

13. N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-( dimethylamino )-7-(2- hydroxy- 4 -methyl Synthesis of pent -2- yl ) thieno [3,2-b] pyridine -2- carboxamide

Put EtOH (5.0 mL), N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino) into a 50 mL round bottom flask. )-7-(2-hydroxy-4-methylpent-3-en-2-yl)thieno[3,2-b]pyridine-2-carboxamide (150.0 mg, 0.3 mmol, 1.0 equivalent), Pd/C (30.0 mg, 0.2 mmol, 0.8 equivalent). _{H 2} (g) is introduced into the above flask. The resulting solution was stirred at 50°C for 2 hours. The solid was filtered out. The resulting mixture was concentrated in vacuo. Obtain 100 mg of N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino)-7-(2- Hydroxy-4-methylpent-2-yl)thieno[3,2-b]pyridine-2-carboxamide (66.3%).

14. N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-( dimethylamino )-7-[(2E)-4 -methyl Synthesis of pent -2- en -2- yl ] thieno [3,2-b] pyridine -2- carboxamide

Put pyridine (3.0 mL), N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino) into a 50 mL round bottom flask. )-7-(2-hydroxy-4-methylpent-2-yl)thieno[3,2-b]pyridine-2-carboxamide (100.0 mg, 0.2 mmol, 1.0 equivalent), SOCl ₂ (0.5 mL). The resulting solution was stirred at 0°C for 1 hour. The reaction was then quenched by adding water/ice. The resulting solution was extracted with 3×20 mL ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Obtained 70 mg of N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino)-7-[(2E )-4-Methylpent-2-en-2-yl]thieno[3,2-b]pyridine-2-carboxamide (72.8%).

15. N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-( dimethylamino )-7-(4 -methylpentan -2- Synthesis of phenyl ) thieno [3,2-b] pyridine -2- carboxamide

Put EtOH (5.0 mL), N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino) into a 50 mL round bottom flask. )-7-[(2E)-4-methylpent-2-en-2-yl]thieno[3,2-b]pyridine-2-carboxamide (70.0 mg, 0.16 mmol, 1.0 equivalent), Pd/C (20.0 mg, 0.19 mmol, 1.2 equivalents). _{H 2} (g) is introduced into the above flask. The resulting solution was stirred at room temperature for 2 hours. The solid was filtered out. The resulting mixture was concentrated in vacuo. Purify the crude product by flash preparative HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H ₂ O and CH ₃ CN (increase from 20% CH ₃ CN to 90% in 20 minutes ); Detector, 220 nm. 12.2 mg of N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(dimethylamino)-7-(4- Methylpent-2-yl)thieno[3,2-b]pyridine-2-carboxamide (17.3%). (ES, m/z): 438 [M+H] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.65 (d, J = 4.8 Hz, 1H), 7.38-7.29 (m, 2H) , 7.28-7.16 (m, 1H), 6.97-6.94 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.31 (t, J = 5.6 Hz, 1H), 4.38-4.36 (m, 1H) ), 4.27-4.24 (m, 1H), 3.24-2.22 (m, 1H), 2.99 (s, 6H), 2.45-2.28 (m, 1H), 2.27-2.11 (m, 1H), 1.90-1.75 (m , 1H), 1.66-1.35 (m, 6H), 0.99- 0.90 (m, 6H) ppm.

Put NMP (5.0 mL) and trifluoromethanesulfonic acid 2-[[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]carbamidine into an 8 mL sealed test tube Yl]-3-(dimethylamino)thieno[3,2-b]pyridin-7-yl ester (200.0 mg, 0.4 mmol, 1.0 equivalent), 4,4-difluoropiperidine (400.0 mg, 3.3 mmol, 8.3 equivalents). The final reaction mixture was irradiated by microwave radiation at 150°C for 30 minutes. Purify the crude product by flash preparative HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, H ₂ O and CH ₃ CN (increase from 20% CH ₃ CN to 90% in 20 minutes ); Detector, 254 nm. Obtained 24.9 mg of 7-(4,4-difluoropiperidin-1-yl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4 as a pale yellow solid -Yl]-3-(dimethylamino)thieno[3,2-b]pyridine-2-carboxamide (13.3%). (ES, m/z): 473 [M+H] ⁺ ; ¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.51 (d, J = 5.4 Hz, 1H), 7.38-7.28 (m, 1H ), 7.28-7.16 (m, 1H), 7.00-6.91 (m, 2H), 6.86 (d, J = 8.3 Hz, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.38-4.32 (m, 1H), 4.27-4.23 (m, 1H), 3.67-3.58 (m, 4H), 2.97 (s, 6H), 2.44-2.11 (m, 6H) ppm.

The following compounds can be prepared according to Scheme 11 below: 115, 116, 117, 118, 237, 115-INT-3, 239, 239-INT-1, 237A.

Process 11

Exemplary procedures for compounds 115 and 116 : Synthesis of 4-(3,5 -difluorophenyl ) thieno [3,2-d] pyrimidine as a white solid

酸(6.0 g，38.0 mmol，1.3當量)、Pd(dppf)Cl₂ (2.1 g，3.0 mmol，0.1當量)、K₃ PO₄ (12.4 g，59.0 mmol，2當量)、二噁烷(100.0 mL)、H₂ O (10.0 mL)。將所得溶液在80℃攪拌隔夜。濃縮所得混合物。將殘餘物施加至具有乙酸乙酯/石油醚(1/10至1/4)之矽膠管柱上。得到7.8 g呈白色固體狀之4-(3,5-二氟苯基)噻吩并[3,2-d]嘧啶(粗物質)。(ES, m/z)：249 [M+H]⁺ 。Put 4-chlorothieno[3,2-d]pyrimidine (5.0 g, 29.3 mmol, 1.0 equivalent) and 3,5-difluorophenyl into a 250 mL round-bottomed flask that was purged and maintained with an inert nitrogen atmosphere.

Acid (6.0 g, 38.0 mmol, 1.3 equivalents), Pd(dppf)Cl ₂ (2.1 g, 3.0 mmol, 0.1 equivalents), K ₃ PO ₄ (12.4 g, 59.0 mmol, 2 equivalents), dioxane (100.0 mL ), H ₂ O (10.0 mL). The resulting solution was stirred at 80°C overnight. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/10 to 1/4). 7.8 g of 4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine (crude material) was obtained in the form of a white solid. (ES, m/z): 249 [M+H] ⁺ .

1. Synthesis of 7- bromo- 4-(3,5 -difluorophenyl ) thieno [3,2-d] pyrimidine

Put 4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine (3.50 g, 14.1 mmol, 1.0 equivalent), Br ₂ (11.30 g, 70.6 mmol) into a 250 mL round bottom flask , 5.0 equivalents), AcOH (52.0 mL). The resulting solution was stirred at 70°C for 2 days. The reaction was then quenched by pouring into 500 mL of iced NaHCO ₃ aqueous solution. The resulting solution was extracted with 2×500 mL ethyl acetate. The EA mixture was washed with 2×500 mL NaCHO ₃ aqueous solution and 1×500 mL NaS ₂ SO ₃ aqueous solution. The resulting EA mixture was washed with 1×500 mL brine. The EA mixture was dried over anhydrous sodium sulfate. The solid was filtered out. The filtrate was concentrated. 4 g of 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine was obtained as a pale yellow solid.

2. Synthesis of 7- bromo- 4-(3,5 -difluorophenyl ) thieno [3,2-d] pyrimidine -6- carboxylic acid

Put 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine (1.3 g, 1.0 Equivalent), THF (130.0 mL). Then LDA (4.0 mL, 1.5 equivalents) was added dropwise at -78°C with stirring. The resulting solution was stirred at -78°C for 30 minutes. _{CO 2 is} supplied thereto at -50°C. The resulting solution was allowed to react for another 2 hours at -50°C with stirring. The resulting solution was allowed to react for another 2 hours at room temperature with stirring. The reaction was then quenched by adding 100 mL of water. The solid was collected by filtration. 500 mg of 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid was obtained as a pale yellow solid.

3. 7- bromo- 4-(3,5 -difluorophenyl )-N-[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ] thieno [3 ,2-d] Pyrimidine -6- formamide synthesis

Put 7-bromo-4-(3,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid (1.6 g, 4.3 mmol, 1.0 equivalent) into a 250 mL round bottom flask, (4S)-3,4-Dihydro-2H-1-benzopiperan-4-amine (707.4 mg, 4.7 mmol, 1.1 equivalents), HATU (3278.2 mg, 8.6 mmol, 2 equivalents), DIEA (1392.8 mg , 10.7 mmol, 2.5 equivalents), DMF (50.0 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 50 mL of water. The solid was collected by filtration. Obtain 1.1 g of 7-bromo-4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4- as a yellow solid Base]thieno[3,2-d]pyrimidine-6-carboxamide (50.8%). (ES, m/z): 502 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.49 (s, 1H), 9.40 (d, J = 8.1 Hz, 1H) , 7.82 (d, J = 6.6 Hz, 2H), 7.65 (t, J = 9.0 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.20 (t, J = 6.9 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 5.29 (d, J = 6.6 Hz, 1H), 4.29 (s, 2H), 42.25-2.13 (m, 2H) ppm.

4. 4-(3,5 -Difluorophenyl )-N-[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ]-7-( prop- 1- Synthesis of ( en -2- yl ) thieno [3,2-d] pyrimidine -6-carboxamide

Put 7-bromo-4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H- into a 50 mL round bottom flask purged and maintained with an inert nitrogen atmosphere. 1-Benzopiperan-4-yl]thieno[3,2-d]pyrimidine-6-carboxamide (57.0 mg, 0.1 mmol, 1.0 equivalent), trifluoro(prop-1-en-2-yl) )-λ4-potassium borane (38.0 mg, 0.3 mmol, 2.0 equivalents), Pd(dppf)Cl ₂ (15.0 mg, 0.02 mmol, 0.2 equivalents), K ₃ PO ₄ (48.0 mg, 0.3 mmol, 2.0 equivalents), Dioxane (3.0 mL), H ₂ O (0.3 mL). The resulting solution was stirred at 80°C overnight. The crude product was purified by flash preparative HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, which increased from ACN/H ₂ O=20/80 to ACN/H ₂ O= within 15 minutes 100/0; detector, 254 nm. Obtained 27.8 mg of 4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-7 as an off-white solid -(Pro-1-en-2-yl)thieno[3,2-d]pyrimidine-6-carboxamide. (ES, m/z): 464 [M+H] ⁺ ; ¹ H-NMR (300 MHz, CD ₃ OD): δ = 9.34 (s, 1H), 7.81-7.78 (m, 2H), 7.49 (d , J = 7.2 Hz, 1H), 7.26-7.21 (m, 1H), 7.09-7.02 (m, 1H), 6.97-6.87 (m, 2H), 5.60 (t, J = 1.5 Hz, 1H), 5.38- 5.35 (m, 1H), 5.27 (s, 1H), 4.34-4.31 (m, 1H), 4.19-4.12 (m, 1H), 2.39-2.36 (m, 1H), 2.22-2.19 (m, 4H) ppm .

5. 4-(3,5 -Difluorophenyl )-N-[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ]-7- isopropylthieno Synthesis of [3,2-d] pyrimidine -6- formamide

Put 4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]- into a 50 mL round bottom flask 7-(Pro-1-en-2-yl)thieno[3,2-d]pyrimidine-6-carboxamide (90.0 mg, 0.2 mmol, 1.0 equivalent), PtO ₂ (90.0 mg, 1.0 equivalent), EA (20.0 mL). The mixture was rinsed 6 times _{with H 2.} The resulting solution was stirred at room temperature overnight. The solid was filtered out. The filtrate was concentrated. The crude product was purified by flash preparative HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, which increased from ACN/H ₂ O=30/70 to ACN/H ₂ O= within 15 minutes 80/20; detector, 254 nm. Obtained 27.7 mg of 4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-7 as a white solid -Isopropylthieno[3,2-d]pyrimidine-6-carboxamide. (ES, m/z): 466 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.40 (s, 1H), 9.34 (d, J = 6.9 Hz, 1H) , 7.79 (d, J = 6.0 Hz, 2H), 7.64-7.61 (m, 1H), 7.27-7.16 (m, 2H), 6.96-6.93 (m, 1H), 6.82-6.79 (m, 1H), 5.30 (s, 1H), 4.26 (m, 2H), 3.85-3.81 (m, 1H), 2.30-1.98 (m, 2H), 1.51 (m, 6H) ppm.

6. 4-(3,5 -Difluorophenyl )-N-[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ]-7-( dimethylamino ) thieno [3,2-d] pyrimidine-6-carboxylic Amides of

Put 7-bromo-4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4- into a 50 mL sealed test tube Yl]thieno[3,2-d]pyrimidine-6-carboxamide (80.0 mg, 0.16 mmol, 1.0 equivalent), dimethylamine (2 M in THF, 50.0 mL). The resulting solution was stirred at 110°C for 4 hours. The resulting mixture was concentrated. The crude product was purified by flash preparative HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, which increased from ACN/H ₂ O=20/80 to ACN/H ₂ O= within 15 minutes 90/10; detector, 254 nm. Obtained 5 mg of 4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-7 as a white solid -(Dimethylamino)thieno[3,2-d]pyrimidine-6-carboxamide. (ES, m/z): 467 [M+H] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 10.36 (d, J = 8.1 Hz, 1H), 9.28 (s, 1H), 7.76 (dd, J = 8.1, 2.1 Hz, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.26-7.20 (m, 1H), 7.08-7.01 (m, 1H), 6.96-6.88 (m, 2H ), 5.42-5.38 (m, 1H), 4.39-4.33 (m, 1H), 4.28-4.20 (m, 1H), 2.99 (s, 6H), 2.44-2.38 (m, 1H), 2.23-2.16 (m , 1H) ppm.

7. 4-(3,5 -Difluorophenyl )-N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-7-( morpholine -4 - yl) thieno [3,2-d] pyrimidine-6-synthesis of Amides of

Put 7-bromo-4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H- into a 50 mL round bottom flask purged and maintained with an inert nitrogen atmosphere 1-Benzopiperan-4-yl]thieno[3,2-d]pyrimidine-6-carboxamide (100.0 mg, 0.2 mmol, 1.0 equivalent), morpholine (174.0 mg, 2.0 mmol, 10.0 equivalent) , Pd ₂ (dba) ₃ (20.0 mg, 0.02 mmol, 0.1 equivalent), Xantphos (23.0 mg, 0.04 mmol, 0.2 equivalent), toluene (10.0 mL), Cs ₂ CO ₃ (130.0 mg, 0.4 mmol, 2.0 equivalent) . The resulting solution was stirred at 110°C for 3 hours. The solid was filtered out. The filtrate was concentrated. The crude product was purified by flash preparative HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, which increased from ACN/H ₂ O=10/90 to ACN/H ₂ O= within 15 minutes 90/10; detector, 254 nm. Obtained 47.4 mg of 4-(3,5-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-7 as a yellow solid -(Morpholin-4-yl)thieno[3,2-d]pyrimidin-6-carboxamide. (ES, m/z): 509 [M+H] ⁺ ; ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 10.64 (d, J = 6.9 Hz, 1H), 9.31 (s, 1H), 7.80 (dd, J = 8.1, 2.1 Hz, 2H), 7.31-7.27 (m, 2H), 7.11-7.05 (m, 1H), 6.99-6.93 (m, 2H), 5.35-5.30 (m, 1H), 4.43 -4.38 (m, 1H), 4.27-4.19 (m, 1H), 3.52-3.39 (m, 8H), 2.41-2.33 (m, 2H) ppm.

The following compounds can be prepared according to the following scheme 12 and the following detailed procedures: 201, 203, 206, 208, 209, 211, 211-0A, 213, 214, 216, 217, 220, 221, 222, 223, 229, 231, 232, 236, 238, 240, 241, 242, 243, 245, 246, 247, 248, 249, 250, 255, 255-0A, 257, 268, 268-4, 347, 348. Process 12

Exemplary procedure for compound 201 : 1. Synthesis of 3- bromo -7 -chlorothieno [3,2-b] pyridine

Put 7-chlorothieno[3,2-b]pyridine (25.0 g, 147.3 mmol, 1.0 equivalent), CHCl ₃ (4166.6 mL, 34903.0 mmol, 350.5 equivalent), KHSO _{4 into a 3000 mL 3-neck round bottom flask} (30.1 g, 221.0 mmol, 1.5 equivalents), NaHCO ₃ (12.3 g, 147.4 mmol, 1.0 equivalents), MgSO ₄ (26.6 g, 221.0 mmol, 1.5 equivalents), Br ₂ (235.5 g, 1473.8 mmol, 10.0 equivalents). The resulting solution was stirred at 70°C for 16 hours. The reaction was cooled to room temperature. The reaction was then quenched by adding 500 mL of Na ₂ S ₂ O ₃ (aqueous solution). The resulting solution was extracted with 2×1 L DCM. The organic layers were combined, dried, and concentrated in vacuo. 30 g of 3-bromo-7-chlorothieno[3,2-b]pyridine (81.9%) was obtained as a yellow solid.

2. Synthesis of 3- bromo -7 -chlorothieno [3,2-b] pyridine -2- carboxylic acid

Put 3-bromo-7-chlorothieno[3,2-b]pyridine (30.0 g, 1.0 equivalent), THF (1000.0 mL), LDA (84.0 mL, 1.5 equivalent) into a 2000 mL flask. The resulting solution was stirred at -78°C for 2 hours. _{CO 2} was introduced into the above solution at -78 degrees Celsius for 2 hours. The reaction was then quenched by adding 500 mL NH _{4 Cl.} The solid was collected by filtration. 18 g of 3-bromo-7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (51.1%) was obtained as a yellow solid.

3. 3- Bromo -7- chloro- N-[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ] thieno [3,2-b] pyridine -2- Synthesis of Formamide

Put 3-bromo-7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (25.0 g, 85.4 mmol, 1.0 equivalent), HATU (48.7 g, 128.2 mmol, 1.5 Equivalent), DMF (300.0 mL), DIEA (33.1 g, 256.4 mmol, 3.0 equivalents), (4S)-3,4-dihydro-2H-1-benzopiperan-4-amine (19.1 g, 128.2 mmol , 1.5 equivalents). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 500 mL of water. The solid was collected by filtration. 30 g of 3-bromo-7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]thieno[3,2- b] Pyridine-2-carboxamide (82.8%).

4. 7- chloro- N-[(4S)-3,4 -dihydro- 2H-1 -benzopiperan- 4 -yl ]-3-( prop- 1 -en -2- yl ) thieno [ Synthesis of 3,2-b] pyridine -2- carboxamide

Put 3-bromo-7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4- into a 500 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere Yl]thieno[3,2-b]pyridine-2-carboxamide (5.0 g, 11.8 mmol, 1.0 equivalent), trifluoro(prop-1-en-2-yl)-λ4-borane potassium (2.6 g, 17.7 mmol, 1.5 equivalents), Pd(dppf)Cl ₂ (0.8 g, 1.2 mmol, 0.1 equivalents), K ₃ PO ₄ (5.0 g, 23.6 mmol, 2.0 equivalents), dioxane (100 mL), H ₂ O (10 mL). The resulting solution was stirred at 90°C for 3 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:10). Obtained 2.8 g of 7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(prop-1-ene-2 as a yellow solid -Yl)thieno[3,2-b]pyridine-2-carboxamide (61.6%).

5. 7-Chloro -N - [(4S) -3,4- dihydro -2H-1- benzopyran-4-yl] -3-isopropyl-thieno [3,2-b] pyridin - synthesis of Amides of 2-

Put 7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-(propyl) in the form of a yellow solid in a 1000 mL round bottom flask. -1-En-2-yl)thieno[3,2-b]pyridine-2-carboxamide (2.50 g, 6.5 mmol, 1.0 equivalent), EA (500.0 mL), Pt ₂ O (1.5 g). The flask was evacuated and flushed with nitrogen three times, followed by a hydrogen flush. The mixture was stirred at 40°C for 3 h under a hydrogen atmosphere (balloon). The reaction mixture was cooled to room temperature. The solid was filtered out. The filtrate was concentrated. Obtain 1.2 g of 7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3-isopropylthieno[3, 2-b] Pyridine-2-carboxamide (59.7%).

6. N-[(4S)-3,4 -Dihydro- 2H-1 -benzopiperan- 4 -yl ]-7-(4- fluoro- 2,6 -dimethylphenyl )-3- Synthesis of isopropylthieno [3,2-b] pyridine -2- carboxamide

Put 7-chloro-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-3- into a 20 mL microwave tube purged and maintained with an inert nitrogen atmosphere Isopropylthieno[3,2-b]pyridine-2-carboxamide (100.0 mg, 0.2 mmol, 1.0 equivalent), DME (3.00 mL), 2-(4-fluoro-2,6-dimethyl Phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborole (162.0 mg, 0.6 mmol, 2.5 equivalents), Pd(dtbpf)Cl ₂ (17.00 mg, 0.026 mmol, 0.1 equivalent), K ₃ PO ₄ (137.0 mg, 0.6 mmol, 2.5 equivalents), H ₂ O (0.50 mL). The final reaction mixture was irradiated by microwave radiation at 100°C for 0.5 hour. The resulting mixture was concentrated. The crude product was purified by flash preparative HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, CH ₃ CN/0.05% NH ₃ .H ₂ O=100%; detector, 254 and 220 nm. Obtained 38.9 mg of N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-7-(4-fluoro-2,6-dimethyl as an off-white solid Phenyl)-3-isopropylthieno[3,2-b]pyridine-2-carboxamide (31.7%). (ES, m/z): 475 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.03 (d, J = 7.8 Hz, 1H), 8.84 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 3.9 Hz, 1H), 7.20-7.09 (m, 4H), 6.91-6.77 (m, 2H), 5.24-5.22 (m, 1H), 4.23 (s, 2H) ), 3.93 (t, J = 6.9 Hz, 1H), 2.12-2.04 (m, 8H), 1.53 (s, 6H) ppm.

Exemplary procedure for compound 255 :

Put 7-(cyclohex-1-en-1-yl)-N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl into a 100 mL round bottom flask ]-3-isopropylthieno[3,2-b]pyridine-2-carboxamide (50.0 mg, 0.1 mmol, 1.0 equivalent), THF (10.0 mL), BH ₃ -THF (1M in THF) (2.5 mL, 26.1 mmol, 226.0 equivalents). The resulting solution was stirred at room temperature for 1 hour. _{Then H 2} O ₂ (30%) (2.50 mL, 107.3 mmol, 928.3 equivalents) and NaHCO ₃ (5 mL) were dropped into the flask. The resulting solution was allowed to react for another 30 minutes at room temperature with stirring. The resulting solution was diluted with 50 mL DCM. Separate the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC with the following conditions (2#SHIMADZU (HPLC-01)): column, SunFire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; mobile phase, water and ACN (in From 16% phase B to 40% within 7 minutes); detector, UV 254 nm. Obtained 15 mg of N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-7-(1-hydroxycyclohexyl)-3-isopropyl as a white solid Thieno[3,2-b]pyridine-2-carboxamide (28.8%) and 20 mg of N-((S)-𠳭alkyl-4-yl)-7-(2-hydroxyl) as a white solid Cyclohexyl)-3-isopropylthieno[3,2-b]pyridine-2-carboxamide (38.4%).

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.75 (s, 1H), 7.41 (s, 1H), 7.32-7.29 (m, 1H), 7.25-7.21 (m, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.21 (s, 1H), 5.36 (s, 1H), 5.00 (d, J = 36.9 Hz, 1H), 4.41-4.33 (m, 1H), 4.29-4.21 (m, 1H), 4.17-4.06 (m, 1H), 2.91 (dd, J = 13.8, 11.7 Hz, 1H), 2.46-2.35 (m, 1H), 2.22-2.10 (m, 3H), 1.97 (d, J = 13.2 Hz, 1H), 1.83 (d, J = 14.4 Hz, 1H), 1.76 (s, 2H), 1.57 (s, 6H), 1.31 (s, 2H) ppm。 Put N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-7-(1-hydroxycyclohexyl)-3-iso into a 50 mL round bottom flask Propylthieno[3,2-b]pyridine-2-carboxamide (15.0 mg, 0.03 mmol, 1.0 equivalent), DCM (2.0 mL). Then DAST (0.1 mL) was added dropwise at 0°C with stirring. The resulting solution was stirred at 25°C for 1 hour. The reaction was then quenched by adding MeOH (0.5 mL). The resulting mixture was concentrated in vacuo. Purify the crude product by preparative HPLC with the following conditions (2#SHIMADZU (HPLC-01)): column, SunFire Prep C18 OBD column, 19×150 mm 5 μm 10 nm; mobile phase, water and ACN (in From 16% CH ₃ CN to 40% within 7 minutes); detector, UV 254 nm. Obtained 2.0 mg of N-[(4S)-3,4-dihydro-2H-1-benzopiperan-4-yl]-7-(1-fluorocyclohexyl)-3-isopropyl as a white solid Thieno[3,2-b]pyridine-2-carboxamide (13.2%). ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.81 (s, 1H), 7.61 (s, 1H), 7.46-7.18 (m, 2H), 6.98-6.86 (m, 2H), 6.25 (d, J = 6.9 Hz, 1H), 5.35 (d, J = 5.7 Hz, 1H), 4.36-4.33 (m, 1H), 4.25-4.10 (m, 2H), 2.37-2.34 (m, 1H), 2.35-1.15 (m, 17H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.75 (s, 1H), 7.41 (s, 1H), 7.32-7.29 (m, 1H), 7.25-7.21 (m, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.21 (s, 1H), 5.36 (s, 1H), 5.00 (d, J = 36.9 Hz, 1H), 4.41-4.33 ( m, 1H), 4.29-4.21 (m, 1H), 4.17-4.06 (m, 1H), 2.91 (dd, J = 13.8, 11.7 Hz, 1H), 2.46-2.35 (m, 1H), 2.22-2.10 ( m, 3H), 1.97 (d, J = 13.2 Hz, 1H), 1.83 (d, J = 14.4 Hz, 1H), 1.76 (s, 2H), 1.57 (s, 6H), 1.31 (s, 2H) ppm .

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.95 (d, J = 7.2 Hz, 1H), 7.83 (dd, J = 8.0, 1.2 Hz, 1H), 7.74 (d, J = 1.9 Hz, 2H), 7.54 (dd, J = 7.6, 1.2 Hz, 1H), 7.44-7.34 (m, 2H), 7.28-7.21 (m, 2H), 7.02-6.89 (m, 2H), 5.40-5.27 (m, 1H), 4.47-4.32 (m, 1H), 4.29-4.15 (m, 1H), 3.69-3.48 (m, 4H), 3.42-3.24 (m, 4H), 2.47-2.18 (m, 2H) ppm。

¹ H-NMR (300 MHz, CDCl₃ )：δ = 7.88 (dd, J = 7.9, 1.2 Hz, 1H), 7.67 (d, J = 1.9 Hz, 2H), 7.50 (dd, J = 7.5, 1.2 Hz, 1H), 7.48-7.41 (m, 1H), 7.41-7.34 (m, 2H), 7.32-7.29 (m, 2H), 7.26 (d, J = 5.7 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.77-5.59 (m, 1H), 4.51-4.23 (m, 1H), 3.21- 2.86 (m, 2H), 2.85-2.68 (m, 1H), 2.07-1.86 (m, 1H), 1.53 (dd, J = 7.1, 2.8 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 7.93 (dd, J = 7.9, 1.3 Hz, 1H), 7.55-7.44 (m, 1H), 7.43-7.33 (m, 2H), 7.32 (d, J = 1.6 Hz, 1H), 7.26-7.17 (m, 1H), 7.07-6.97 (m, 2H), 6.97-6.90 (m, 1H), 6.87 (dd, J = 8.2, 1.2 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 5.49-5.27 (m, 1H), 4.46-4.11 (m, 3H), 2.36 (dddd, J = 16.3, 8.3, 5.4, 3.2 Hz, 1H), 2.14 (dtd, J = 14.0, 7.1, 3.1 Hz, 1H), 1.54 (dd, J = 7.1, 2.9 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.40 (s, 1H), 8.06 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 6.82(d, J = 8.4 Hz, 1H), 5.39 (t, J =5.7 Hz, 1H), 4.34-4.29 (m, 2H), 3.66-3.61 (m, 1H), 2.33-2.26 (m, 2H), 1.43-1.39 (m, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.40 (s, 1H), 8.06 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.39 (t, J =5.7 Hz, 1H), 4.34-4.29 (m, 2H), 3.66-3.61 (m, 1H), 2.33-2.26 (m, 2H), 1.43-1.39 (m, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.40 (s, 1H), 8.06 (s, 1H), 7.96(d, J = 8.7 Hz, 1H), 7.60(d, J = 8.7 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.39 (t, J = 5.7 Hz, 1H), 4.34-4.29 (m, 2H), 3.66-3.61 (m, 1H), 2.33-2.26 (m, 2H), 1.43-1.39 (m, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d6)：δ = 8.48 (d, J = 8.7 Hz, 2H), 7.87-7.79 (m, 2H), 7.62-7.56 (m,2H), 7.31-7.15 (m, 3H), 6.95-6.90 (m, 1H), 6.82-6.80 (m, 1H), 5.50 (s, 1H), 5.26-5.19 (m, 1H), 5.13 (s, 1H), 4.27-4.23 (m, 2H), 2.18-2.05 (m, 5H) ppm。   

¹ H-NMR (300 MHz, DMSO-d6)：δ = 9.04 (d, J = 8.4 Hz, 1H), 8.44 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.83-7.79 (m, 1H), 7.58-7.55 (m, 2H), 7.29-7.15 (m, 3H), 6.96-6.90 (m, 1H), 6.81-6.78 (m, 1H), 5.28 (d, J = 7.5 Hz, 1H), 4.30-4.25 (m, 2H), 3.81-3.76 (m, 1H), 2.27-1.95 (m,2 H), 1.47-1.43 (m, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d6)：δ = 10.06 (d, J = 8.1 Hz, 1H), 8.45 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.2 Hz, 2H), 7.33-7.17 (m, 3H), 6.95-6.90 (m, 1H), 6.85 (d, J = 8.1 Hz, 1H), 5.26-5.20 (m, 1H), 4.36-4.30 (m, 1H), 4.24-4.19 (m, 1H), 2.90 (s, 6H), 2.28-2.23 (m, 1H), 2.13-2.08 (m, 1H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 10.44 (s, 1H), 8.04 (dd, J = 8.0, 1.2 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.42 (dd, J = 7.3, 1.1 Hz, 1H), 7.28-7.18 (m, 4H), 7.04-6.80 (m, 3H), 5.29 (s, 1H), 4.50-4.29 (m, 1H), 4.22 (dt, J = 12.0, 6.4 Hz, 1H), 3.41 (d, J = 49.1 Hz, 8H), 2.45-2.24 (m, 2H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.22 (d, J = 8.1 Hz, 1H), 7.61-7.49 (m, 1H), 7.42 (dd, J = 7.3, 1.0 Hz, 1H), 7.24 (s, 1H), 7.20-7.17 (m, 2H), 7.09-7.77 (m, 3H), 6.23 (d, J = 7.4 Hz, 1H), 5.36 (q, J = 5.7 Hz, 2H), 4.36-4.33 (m, 1H), 4.26-4.16 (m, 4H), 3.74-3.58 (m, 2H), 2.55 (q, J = 12.6 Hz, 2H), 2.45-2.32 (m, 1H), 2.31-2.13 (m, 1H), 1.79 (d, J = 13.6 Hz, 3H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 7.66 (dd, J = 7.8, 1.5 Hz, 1H), 7.53-7.41 (m, 2H), 7.25-7.17 (m, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.98-6.82 (m, 3H), 5.97-5.96 (m, 1H), 5.32-5.29 (m, 1H), 4.37-4.30 (m, 1H), 4.21-3.96 (m, 3H), 3.81-3.74 (m, 1H), 3.68-3.61 (m, 1H), 2.49-2.27 (m, 3H), 2.26-2.14 (m, 1H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.68 (d, J = 5.7 Hz, 1H), 7.73-7.62 (m, 2H), 7.57 (d, J = 5.5 Hz, 1H), 7.29-7.18 (m, 3H), 7.03-6.87 (m, 3H), 5.60 (s, 1H), 5.59-5.37 (m, 1H), 5.25 (s, 1H), 4.36-4.33 (m, 1H), 4.21-4.13 (m, 1H), 2.40-2.37 (m, 1H), 2.23-2.15 (m, 4H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.71 (d, J = 5.1 Hz, 1H), 7.96 (d, J = 4.8 Hz, 1H), 7.59-7.57 (m, 2H), 7.31-7.23 (m, 2H), 7.02-6.98 (m, 2H), 6.96-6.89 (m, 1H), 6.29-6.27 (m, 1H), 5.39-5.37 (m, 1H), 4.41-4.35 (m, 1H), 4.26-4.20 (m, 1H), 4.05-4.00 (m, 1H), 2.42-2.38 (m, 4H), 2.36-2.22 (m, 1H), 1.58-1.55 (m, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d6)：δ = 9.87 (d, J = 8.0 Hz, 1H), 8.67 (d, J = 5.5 Hz, 1H), 8.08 (d, J = 5.5 Hz, 1H), 7.74-7.63 (m, 2H), 7.55-7.44 (m, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.24-7.16 (m, 1H), 6.95-6.90 (m, 1H), 6.84-6.82 (m, 1H), 5.27-5.25 (m, 1H), 4.32-4.22 (m, 2H), 2.92 (s, 6H), 2.27-2.22 (m, 1H), 2.14-2.08 (m, 1H) ppm。

¹ H-NMR (300 MHz, DMSO-d6)：δ 10.20 (d, J = 7.1 Hz, 1H), 8.66 (d, J = 5.5 Hz, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.69-7.66 (m, 2H), 7.51-7.47 (m, 1H), 7.36-7.34 (m, 1H), 7.28-7.23 (m, 1H), 6.97-6.87 (m, 2H), 5.18-5.16 (m, 1H), 4.32-4.31 (m, 1H), 4.21-4.18 (m, 1H), 3.47-3.38 (m, 4H), 3.36-3.25 (m, 4H), 2.69 (s, 2H), 2.22-2.08 (m, 2H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.99 (s, 1H), 8.57 (s, 1H), 7.50-7.38 (m, 2H), 7.34-7.25 (m, 1H), 7.25-7.10 (m, 2H), 6.95-6.91 (m, 1H), 6.83 (d, J = 8.3 Hz, 1H), 5.64 (t, J = 1.6 Hz, 1H), 5.30 (d, J = 2.5 Hz, 2H), 4.29-4.24 (m, 2H), 2.38-2.09 (m, 5H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 9.30 (s, 1H), 8.52 (s, 1H), 7.40 (d, J = 6.5 Hz, 2H), 7.30 (d, J = 7.7 Hz, 1H), 7.16 (m,  2H), 6.94 (t, J = 7.4 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 5.33 (t, J = 5.6 Hz, 1H), 4.32-4.28 (m, 2H), 3.94-3.81 (m, 1H), 2.28 (s, 1H), 1.58 (d, J = 7.1 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 9.36 (s, 1H), 8.54 (s, 1H), 7.42-7.38 (m, 2H), 7.35-7.29 (m, 1H), 7.28-7.11 (m, 2H), 6.97-6.64 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.38-4.34 (m, 1H), 4.27-4.24 (m, 1H), 3.00 (s, 5H), 2.37-2.34 (m, 1H), 2.27-2.12 (m, 1H), 1.43-1.21 (m, 2H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 9.43 (s, 1H), 8.55 (s, 1H), 7.47-7.12 (m, 5H), 7.04-6.89 (m, 2H), 5.22 (t, J = 4.5 Hz, 1H), 4.43-4.32 (m, 1H), 4.32-4.17 (m, 1H), 3.57- 3.45 (m, 2H), 3.43-3.36 (m, 2H), 2.31-2.28 (m, 2H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD) δ = 8.88 (s, 1H), 8.05 (s, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.24-7.13 (m, 1H), 6.95 (td, J = 7.5, 1.2 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 5.34 (t, J = 5.7 Hz, 1H), 4.31-4.27 (m, 2H), 3.79 (p, J = 7.1 Hz, 1H), 3.59 (d, J = 11.6 Hz, 2H), 2.47-2.30 (m, 2H), 2.30-2.10 (m, 2H), 1.92 (d, J = 11.1 Hz, 3H), 1.53 (dd, J = 7.2, 2.0 Hz, 6H), 0.98 (dd, J = 6.4, 3.4 Hz, 6H), 0.95-0.71 (m, 2H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.96 (s, 1H), 8.18-8.12 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.25-7.13 (m, 1H), 6.99-6.95 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.34 (t, J = 5.7 Hz, 1H), 4.37-4.22 (m, 2H), 3.80 (p, J = 7.2 Hz, 1H), 3.41 (t, J = 5.7 Hz, 5H), 2.26-2.24 (m, 6H), 1.53 (d, J = 7.2 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.92 (d, J = 4.8 Hz, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.25-7. 23 (m, 1H), 7.02-7.01 (m, 1H), 7.01-6.92 (m, 1H), 6.92-6.89 (m, 1H), 6.26 (d, J = 6.9 Hz, 1H), 5.40-5.37 (m, 1H), 4.37-4.34 (m, 1H), 4.28-4.21 (m, 1H), 4.11-4.07 (m, 1H), 2.41-2.37 (m, 1H), 2.29-2.25 (m, 1H), 1.61-1.54 (m, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.80 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 4.8 Hz, 1H), 7.53-7.43 (m, 2H), 7.30 (dd, J = 7.6, 1.2 Hz, 1H), 7.26-7.15 (m, 2H), 6.94 (td, J = 7.5, 1.2 Hz, 1H), 6.83 (dd, J = 8.3, 1.2 Hz, 1H), 5.52 (t, J = 1.7 Hz, 1H), 5.36-5.21 (m, 2H), 4.36-4.15 (m, 2H), 2.35-2.23 (m, 4H), 2.23-2.08 (m, 1H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.08 (d, J = 8.4 Hz, 1H), 8.86 (d, J = 4.8 Hz, 1H), 7.61-7.46 (m, 4H), 7.24-7.14 (m, 2H), 6.94-6.89 (m, 1H), 6.80 (d, J = 8.1, 1H), 5.27 (q, J = 7.1 Hz, 1H), 4.36-4.07 (m, 2H), 3.96-3.91 (m, 1H), 2.28-2.04 (m, 2H), 1.52 (dd, J = 7.0, 4.7 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.82 (d, J = 4.7 Hz, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.50-7.38 (m, 2H), 7.38-7.14 (m, 3H), 7.04-6.89 (m, 2H), 5.22 (t, J = 4.4 Hz, 1H), 4.45-4.32 (m, 1H), 4.30-4.19 (m, 1H), 3.61-3.39 (m, 6H), 3.39-3.34 (m, 2H), 2.31 (p, J = 4.2 Hz, 2H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.84 (d, J = 4.7 Hz, 1H), 7.61-7.48 (m, 2H), 7.47-7.16 (m, 8H), 7.02-6.85 (m, 2H), 6.24 (d, J = 7.6 Hz, 1H), 5.37 (q, J = 5.9 Hz, 1H), 4.42-4.06 (m, 3H), 2.45-2.18 (m, 2H), 1.65-1.62 (m, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.76 (d, J = 4.8 Hz, 1H), 7.89-7.78 (m, 2H), 7.45 (d, J = 4.8 Hz, 1H), 7.33-7.28 (m, 3H), 7.17 (td, J = 7.9, 1.7 Hz, 1H), 6.93 (td, J = 7.5, 1.2 Hz, 1H), 6.81 (dd, J = 8.2, 1.3 Hz, 1H), 5.33 (t, J = 5.7 Hz, 1H), 4.35-4.24 (m, 2H), 3.88 (p, J = 7.1 Hz, 1H), 2.38-2.08 (m, 2H), 1.58 (dd, J = 7.1, 2.5 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.81 (d, J = 4.7 Hz, 1H), 7.43-7.30 (m, 3H), 7.29 (d, J = 7.6 Hz, 1H), 7.20 - 7.12 (m, 2H), 6.96 - 6.91 (m, 1H), 6.81 (dd, J = 8.3, 1.2 Hz, 1H), 5.28 (t, J = 5.2 Hz, 1H), 4.33 - 7.24 (m, 2H), 2.30 - 2.13 (m, 2H), 1.70 (s, 9H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.79 (d, J = 4.8 Hz, 1H), 7.56 (dd, J = 11.1, 1.8 Hz, 3H), 7.37-7.29 (m, 2H), 7.29-7.18 (m, 3H), 6.99-6.96 (m, 1H), 6.88 (dd, J = 8.3, 1.2 Hz, 1H), 6.60 (d, J = 7.5 Hz, 1H), 5.33 (q, J = 5.8 Hz, 1H), 4.39-4.33 (m, 1H), 4.25-4.20 (m, 1H), 2.46-2.17 (m, 2H), 1.89 (d, J = 4.2 Hz, 6H) ppm。

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.79 (d, J = 4.8 Hz, 1H), 7.56 (d, J = 11.1 Hz, 3H), 7.37-7.29 (m, 2H), 7.29-7.18 (m, 3H), 6.97 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 8.3, 1.2 Hz, 1H), 6.60 (d, J = 7.4 Hz, 1H), 5.33 (q, J = 5.7 Hz, 1H), 4.42-4.29 (m, 1H), 4.25-4.20 (m, 1H), 2.46-2.18 (m, 2H), 1.89 (d, J = 4.2 Hz, 6H), 1.28 (s, 1H), 1.08 (d, J = 1.3 Hz, 1H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.82 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 1.9 Hz, 2H), 7.66 (t, J = 1.9 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 9.1 Hz, 1H), 6.99-6.87 (m, 1H), 6.81 (d, J = 9.0 Hz, 1H), 5.34 (t, J = 6.1 Hz, 1H), 4.28 (t, J = 5.4 Hz, 2H), 3.94-3.91 (m, 1H), 2.37-2.09 (m, 3H), 1.58 (d, J = 7.1 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 8.92 (d, J = 7.2 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 7.61-7.46 (m, 4H), 7.40 (d, J = 4.8 Hz, 1H), 6.91 (d, J = 4.8 Hz, 1H), 5.36 (d, J = 6.6 Hz, 1H), 3.91 (t, J = 7.2 Hz, 1H), 3.05-2.91 (m, 1H), 2.90-2.82 (m, 2H), 2.40-2.34 (m, 1H), 1.50 (dd, J =1.8 , 3.0 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 8.92 (d, J = 7.8 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 7.61-7.46 (m, 4H), 7.40 (d, J = 4.8 Hz, 1H), 6.91 (d, J = 5.1 Hz, 1H), 5.36 (d, J = 6.0 Hz, 1H), 3.91 (t, J = 6.9 Hz, 1H), 3.05-2.98 (m, 1H), 2.90-2.82 (m, 2H), 2.40-2.34 (m, 1H), 1.50 (dd, J =2.1 , 2.1 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.85 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 4.8 Hz, 1H), 729-7.25 (m, 2H), 7.01-6.95 (m, 1H), 6.86 (s, 1H), 6.12 (d, J = 7.8 Hz, 1H), 5.53 (d, J = 4.8 Hz, 1H), 4.15-4.06 (m, 1H). 3.08-2.93 (m, 3H), 2.35-2.25 (m, 1H), 1.61 (d, J = 6.9 Hz, 6H) ppm。   

  ¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.85 (d, J = 4.5 Hz, 1H), 7.35-7.26 (m, 3H), 7.01-6.93 (m, 1H), 6.86 (s, 1H), 6.12 (d, J = 8.1 Hz, 1H), 5.53 (d, J = 5.7 Hz, 1H), 4.15-4.06 (m, 1H). 3.11-2.93 (m, 3H), 2.35-2.25 (m, 1H), 1.61 (d, J = 6.6 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d6)：δ = 9.01 (d, J = 7.8 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 7.61-7.49 (m, 5H), 5.37 (t, J = 6.3 Hz, 1H), 3.92 (t, J = 6.6 Hz, 1H), 3.14-2.83 (m, 3H), 2.50-2.32 (m, 1H), 1.48 (d, J = 7.2 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.92 (d, J = 4.7 Hz, 1H), 7.81 (d, J = 1.9 Hz, 2H), 7.73-7.64 (m, 1H), 7.59 (dd, J = 11.8, 4.9 Hz, 1H), 7.13 (dd, J = 9.0, 3.1 Hz, 1H), 6.97-6.74 (m, 1H), 6.82 (dd, J = 9.1, 4.7 Hz, 1H), 5.29 (t, J = 5.8 Hz, 1H), 4.29-4.24 (m, 2H), 2.93 (s, 2H), 2.26-2.21 (m, 2H), 2.05 (d, J = 5.8 Hz, 1H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.82 (d, J = 4.9 Hz, 1H), 7.78 (d, J = 1.9 Hz, 2H), 7.68 (t, J = 1.9 Hz, 1H), 7.54 (d, J = 4.9 Hz, 1H), 7.18-7.08 (m, 1H), 6.96-6.92 (m, 1H), 6.80 (dd, J = 9.0, 4.8 Hz, 1H), 5.27 (t, J = 5.6 Hz, 1H), 4.36-4.12 (m, 2H), 2.35-2.09 (m, 2H), 1.86 (d, J = 3.2 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.83 (d, J = 4.8 Hz, 1H), 7.77 (d, J = 1.9 Hz, 2H), 7.67 (t, J = 1.9 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 9.2Hz, 1H), 6.94-6.90 (m, 1H), 6.79 (d, J = 9.0 Hz, 1H), 5.27 (t, J = 5.8 Hz, 1H), 4.34-4.18 (m, 2H), 2.01 (d, J = 23.5Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.85 (d, J = 4.8 Hz, 1H), 7.66 (d, J = 1.9 Hz, 2H), 7.55 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 5.7 Hz, 1H), 7.36 (d, J = 4.7 Hz, 1H), 7.28-7.24 (m, 3H), 7.01-6.86 (m, 2H), 5.63-5.56 (m, 1H), 5.39-5.36 (m, 1H), 5.31-5.24 (m, 1H), 4.38-4.34 (m, 1H), 4.19-4.16 (m, 1H), 2.48-2.31 (m, 1H), 2.27-2.11 (m, 4H) ppm。   

¹ H-NMR (300 MHz, DMSO-d ₆ )：δ = 9.52 (d, J = 8.0 Hz, 1H), 8.90 (d, J = 1.7 Hz, 1H), 7.91-7.79 (m, 3H), 7.36-7.11 (m, 2H), 6.95-6.75 (m, 2H), 5.89 (s, 1H), 5.17 (t, J = 6.7 Hz, 1H), 4.34-4.14 (m, 2H), 2.16-2.00 (m, 2H), 1.76 (d, J = 3.1 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.08 (d, J = 8.2 Hz, 1H), 8.93 (d, J = 1.8 Hz, 1H), 7.90 (t, J = 1.9 Hz, 1H), 7.85-7.80 (m, 2H), 7.30-7.22 (m, 1H), 7.21-7.12 (m, 1H), 6.96-6.84 (m, 1H), 6.82-6.74 (m, 1H), 5.16 (q, J = 6.2 Hz, 1H), 4.21 (d, J = 8.4 Hz, 2H), 2.10 (s, 2H), 1.98-1.86 (m, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.08 (d, J = 8.2 Hz, 1H), 8.91 (d, J = 1.8 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.81 (dd, J = 2.0, 0.8 Hz, 2H), 7.25-7.11 (m, 2H), 6.90 (t, J = 7.4, 1H), 6.79 (dd, J = 8.2, 1.2 Hz, 1H), 5.24 (q, J = 6.8 Hz, 1H), 4.25 (q, J = 5.3, 4.5 Hz, 2H), 4.00-3.84 (m, 1H), 2.19-1.99 (m, 2H), 1.50 (dd, J = 7.0, 4.7 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.63 (s, 1H), 8.40 (s, 1H), 7.54 (d,J = 6.4 Hz, 3H), 7.37 (t,J = 7.6 Hz, 1H), 7.23 (d,J = 7.5 Hz, 1H), 7.13-6.98 (m, 2H), 4.39 (d,J = 11.3 Hz, 1H), 4.10-3.92 (m, 2H), 3.87-3.70 (m, 1H), 2.67-2.56 (m, 1H), 2.34 (d,J = 13.6 Hz, 1H), 1.11 (d,J = 5.6 Hz, 3H), 1.01 (d,J = 5.6 Hz, 3H) ppm。

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.36 (d, J = 8.1 Hz, 1H), 8.90 (d, J = 1.6 Hz, 1H), 7.88 (t, J = 1.9 Hz, 1H), 7.79 (d, J = 2.0 Hz, 2H), 7.26-7.11 (m, 2H), 6.90 (t, J = 7.5, 1H), 6.79 (dd, J = 8.2, 1.2 Hz, 1H), 5.18 (q, J = 5.9 Hz, 1H), 4.32-4.14 (m, 2H), 2.20-2.10 (m, 1H), 2.03-1.93 (m, 1H), 1.60 (s, 9H) ppm。

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.39 (d, J = 8.0 Hz, 1H), 8.91 (d, J = 1.6 Hz, 1H), 7.88 (t, J = 1.9 Hz, 1H), 7.79 (dd, J = 1.9, 0.9 Hz, 2H), 7.09-6.96 (m, 2H), 6.87-6.76 (m, 1H), 5.24-5.12 (m, 1H), 4.29-4.13 (m, 2H), 2.18-2.09 (m, 1H), 2.00 (d, J = 2.9 Hz, 1H), 1.60 (s, 9H) ppm。

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.06 (d, J = 8.3 Hz, 1H), 8.91 (d, J = 1.9 Hz, 1H), 7.51 (dd, J = 7.1, 3.0 Hz, 3H), 7.25-7.12 (m, 2H), 6.90 (t, J = 7.5, 1H), 6.79 (dd, J = 8.2, 1.2 Hz, 1H), 5.24 (q, J = 6.7 Hz, 1H), 4.33-4.16 (m, 2H), 4.00-3.85 (m, 1H), 2.19-2.01 (m, 2H), 1.55-1.46 (m, 6H) ppm。

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.83 (d, J = 4.8 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.37-7.26 (m, 2H), 7.00-6.90 (m, 3H), 6.856.80 (m, 1H), 5.61 (s, 1H), 5.36 (t, J = 6.6 Hz, 1H ), 5.27 (s, 1H), 4.33-4.27 (m, 1H), 4.18-4.11 (m, 1H), 2.38-2.31 (m, 1H), 2.24 (s, 3H), 2.14-2.09 (m, 1H), 1.52 (d, J = 8.7 Hz, 1H) ppm。

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 8.85 (d, J = 4.5 Hz, 1H), 8.76 (d, J = 9.3 Hz, 1H), 7.60-7.46 (m, 4H), 7.40 (d, J = 5.1 Hz, 1H), 6.91 (d, J = 5.1 Hz, 1H), 5.04 (d, J = 9.0 Hz, 1H), 3.88 (t, J = 6.9 Hz, 1H), 2.86 (d, J = 15.3 Hz, 1H), 2.66 (d, J = 15.3 Hz, 1H), 1.50 (d, J = 6.9 Hz, 6H), 1.28 (s, 3H), 1.14 (s, 3H) ppm。

¹ H-NMR (300 MHz, DMSO-d6)：δ = 8.84 (d, J = 4.8 Hz, 1H), 8.76 (d, J = 9.3 Hz, 1H), 7.60-7.46 (m, 4H), 7.40 (d, J = 5.1 Hz, 1H), 6.90 (d, J = 4.8 Hz, 1H), 5.03 (d, J = 9.0 Hz, 1H), 3.87 (t, J = 6.9 Hz, 1H), 2.86 (d, J = 15.3 Hz, 1H), 2.65 (d, J = 15.3 Hz, 1H), 1.50 (d, J = 6.9 Hz, 6H), 1.28 (s, 3H), 1.14 (s, 3H) ppm。

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.09 (d, J = 8.1 Hz, 1H), 8.92 (d, J = 1.8 Hz, 1H), 7.59-7.48 (m, 3H), 7.09-6.95 (m, 2H), 6.88-6.78 (m, 1H), 5.23 (q, J = 6.7 Hz, 1H), 4.30-4.15 (m, 2H), 4.03-3.86 (m, 1H), 2.20-2.00 (m, 2H), 1.58-1.40 (m, 6H) ppm。

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.10 (d, J = 8.2 Hz, 1H), 9.00-8.86 (m, 1H), 7.52 (d, J = 7.4 Hz, 3H), 7.14-6.94 (m, 2H), 6.80 (dd, J = 9.1, 4.8 Hz, 1H), 5.16 (d, J = 6.3 Hz, 1H), 4.21 (s, 2H), 2.10 (s, 1H), 1.93 (dd, J = 23.2, 7.3 Hz, 7H) ppm。

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.71 (d, J = 4.8 Hz, 1H), 7.36-7.29 (m, 1H), 7.26-7. 23(m, 1H), 7.02-6.96 (m, 1H), 6.92-6.90 (m, 1H), 6.27 (d, J = 7.8 Hz, 1H), 5.00 (d, J = 6.9 Hz, 1H), 4.38-4.34 (m, 1H), 4.29-4.25 (m, 1H), 4.14-4.09 (m, 1H), 2.41-2.36 (m, 1H), 2.31-2.27 (m, 1H), 1.61-1.56 (m, 6H), 1.55 (s, 9H) ppm。

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.39 (d, J = 8.0 Hz, 1H), 8.91 (d, J = 1.6 Hz, 1H), 7.59-7.43 (m, 3H), 7.11-6.98 (m, 2H), 6.88-6.78 (m, 1H), 5.17 (d, J = 7.3 Hz, 1H), 4.31-4.13 (m, 2H), 2.22-2.07 (m, 1H), 2.05-1.91 (m, 1H), 1.60 (s, 9H) ppm。

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.78 (s, 1H), 7.26-7.17 (m, 2H), 7.06-6.83 (m, 5H), 6.14 (d, J = 7.5 Hz, 1H), 5.31 (q, J = 5.9 Hz, 1H), 4.35-4.28 (m, 1H), 4.21-4.13 (m, 1H), 4.08-3.99 (m, 1H), 2.42-2.27 (m, 1H), 2.23-2.15 (m, 1H), 1.57 (dd, J = 7.1, 2.6 Hz, 6H) ppm。

¹ H-NMR (300 MHz, CDCl₃ )：δ = 10.50 (d, J = 7.7 Hz, 1H), 8.80 (d, J = 4.7 Hz, 1H), 7.40-7.28 (m, 5H), 7.26-7.21 (m, 2H), 7.05-6.86 (m, 3H), 6.50-6.33 (m, 1H), 5.40 (q, J = 6.4 Hz, 1H), 4.38-4.34 (m, 1H), 4.30-4.27 (m, 1H), 3.03 (s, 6H), 2.51-2.35 (m, 1H), 2.23-2.20 (m, 1H), 1.41-1.16 (m, 1H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.63 (d, J = 4.8 Hz, 1H), 7.38-7.27 (m, 2H), 7.27-7.16 (m, 1H), 6.96-6.93 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.43-4.30 (m, 1H), 4.27-4.22 (m, 1H), 2.98 (s, 6H), 2.96-2.83 (m, 1H), 2.39-2.32 (m, 1H), 2.21-2.17 (m, 1H), 2.05 (s, 1H), 2.00 (s, 3H), 1.93 (s, 1H), 1.86 (d, J = 12.5 Hz, 1H), 1.77-1.56 (m, 3H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.66 (d, J = 4.8 Hz, 1H), 7.38-7.29 (m, 2H), 7.28-7.16 (m, 1H), 6.97-6.91 (m, 1H), 6.86 (d, J = 8.2 Hz, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.39-4.35 (m, 1H), 4.28-4.23 (m, 1H), 3.09 (d, J = 9.3 Hz, 1H), 2.99 (s, 6H), 2.56-2.50 (m, 1H), 2.45-2.28 (m, 1H), 2.27-1.95 (m, 8H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.66 (d, J = 4.8 Hz, 1H), 7.38-7.29 (m, 2H), 7.28-7.16 (m, 1H), 6.97-6.92(M, 1H), 6.86 (dd, J = 8.2, 1.2 Hz, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.38-4.33 (m, 1H), 4.27-4.23 (m, 1H), 2.98 (s, 7H), 2.45-2.28 (m, 2H), 2.27-2.11 (m, 5H), 1.74-1.62 (m, 4H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 7.89-7.77 (m, 3H), 7.70 (t, J = 1.9 Hz, 1H), 7.35-7.26 (m, 1H), 7.24-7.12 (m, 1H), 6.94 (td, J = 7.5, 1.3 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.34 (t, J = 5.6 Hz, 1H), 4.37-4.20 (m, 2H), 3.88 (p, J = 7.0 Hz, 1H), 2.39-2.11 (m, 2H), 2.05 (s, 2H), 1.59 (d, J = 7.1 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.42 (d, J = 5.5 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.27-7.15 (m, 1H), 6.96-6.93 (m, 1H), 6.88-6.78 (m, 2H), 5.29 (t, J = 5.6 Hz, 1H), 4.38-4.32 (m, 1H), 4.27-4.22 (m, 1H), 3.98 (d, J = 12.2 Hz, 2H), 2.95 (s, 6H), 2.52 (t, J = 11.9 Hz, 2H), 2.44-2.28 (m, 1H), 2.19-2.16 (m, 1H), 1.31 (s, 2H), 1.01 (d, J = 6.4 Hz, 6H), 0.94-0.79 (m, 2H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 8.43 (d, J = 5.5 Hz, 1H), 7.33 (d, J = 7.6, 1.6 Hz, 1H), 7.27-7.16 (m, 1H), 6.96-6.92 (m, 1H), 6.89-6.80 (m, 2H), 5.29 (t, J = 5.6 Hz, 1H), 4.38-4.32 (m, 1H), 4.26-4.24 (m, 1H), 3.49 (t, J = 5.1 Hz, 4H), 2.95 (s, 6H), 2.44-2.28 (m, 1H), 2.26-2.10 (m, 1H), 1.82 (s, 2H), 1.80 (s, 3H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 8.93 (d, J = 8.4 Hz, 1H), 8.55 (s, 1H), 7.24-7.15 (m, 2H), 6.92 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 5.24 (m, 1H), 4.29-4.24 (m, 2H), 3.99 (s, 3H), 3.89-3.84 (m, 1H), 3.40-3.23 (m, 4H), 2.16-2.05 (m, 6H), 1.48-1.45 (m, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.20 (d, J = 7.8 Hz, 1H), 7.84-7.82 (m, 2H), 7.72-7.66 (m, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 5.50 (s, 1H), 5.30-5.25 (m, 2H), 4.30-4.22 (m, 2H), 2.29 (s, 3H), 2.19-2.17 (m, 1H), 2.07-2.00 (m, 1H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.46 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.8 Hz, 2H), 7.79-7.65 (m, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.22-7.17 (m, 1H), 6.94 (t, J = 7.2 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 5.30 (q, J = 6.6 Hz, 1H), 4.27 (t, J = 4.8 Hz, 2H), 3.89-3.80 (m, 1H), 2.22-2.02 (m, 2H), 1.51 (dd, J = 7.0, 5.0 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 9.33 (s, 1H), 7.59-7.56 (m, 2H), 7.32-7.18 (m, 3H), 6.95 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 5.83 (s, 1H), 5.38 (s, 1H), 5.30 (t, J = 5.1 Hz, 1H), 4.32-4.23 (m, 2H), 2.37 (s, 3H), 2.31-2.21 (m, 2H), 2.20-2.15 (m, 1H) ppm。   

¹ H-NMR (300 MHz, CD₃ OD)：δ = 9.29 (s, 1H), 7.57-7.54 (m, 2H), 7.33-7.16 (m, 3H), 6.98-6.93 (m, 1H), 6.83 (dd, J = 8.1, 0.9 Hz, 1H), 5.36 (t, J = 5.4 Hz, 1H), 4.33-4.27 (m, 2H), 4.00-3.95 (m, 1H), 2.34-2.30 (m, 1H), 2.22-2.16 (m, 1H), 1.65 (dd, J = 6.9, 3.0 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.11 (d, J = 8.4 Hz, 1H), 8.90 (d, J = 4.5 Hz, 1H), 7.80-7.74 (m, 1H), 7.62 (d, J = 4.5 Hz, 1H), 7.46-7.40 (m, 1H), 7.22-7.13 (m, 2H), 6.90 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 5.27-5.21 (m, 1H), 4.24 (t, J = 5.1 Hz, 2H), 3.99-3.85 (m, 1H), 2.18-2.00 (m, 2H), 1.54-1.50 (m, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.05 (d, J = 8.4 Hz, 1H), 8.87 (d, J = 4.8 Hz, 1H), 7.84 (dd, J = 6.3, 3.6 Hz, 1H), 7.57-7.55 (m, 2H), 7.48 (d, J = 4.8 Hz, 1H), 7.20-7.13 (m, 2H), 6.89 (t, J = 6.6 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 5.26-5.20 (m, 1H), 4.23 (s, 2H), 3.98-3.88 (m, 1H), 2.17-1.99 (m, 2H), 1.52 (dd, J = 6.9,4.8 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.10 (d, J = 8.1 Hz, 1H), 8.89 (d, J = 4.5 Hz, 1H), 7.67-7.57 (m, 2H), 7.52-7.47 (m, 2H), 7.21-7.13 (m, 2H), 6.89 (t, J = 6.9 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 5.27-5.20 (m, 1H), 4.23 (s, 2H), 3.93-3.89 (m, 1H), 2.15-2.04 (m, 2H), 1.56-1.51 (m, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.09 (d, J = 8.1 Hz, 1H), 8.88 (d, J = 4.8 Hz, 1H), 7.72-7.66 (m, 1H), 7.57 (d, J = 4.5 Hz, 1H), 7.37 (t, J = 8.4 Hz, 2H), 7.22-7.13(m, 2H), 6.90 (td, J = 7.5, 0.9 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 5.25-5.23 (m, 1H), 4.26-4.22 (m, 2H), 3.93-3.89 (m, 1H), 2.16-2.03 (m, 2H), 1.55-1.51 (m, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 9.11 (d, J = 8.3 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 7.84 (q, J = 1.3 Hz, 3H), 7.61 (d, J = 4.8 Hz, 1H), 7.28-7.20 (m, 1H), 7.20-7.11 (m, 1H), 6.95-6.91 (m, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.27 (q, J = 6.7 Hz, 1H), 4.28-4.25 (m, 2H), 3.96-3.92 (m, 1H), 2.20-1.99 (m, 2H), 1.51 (dd, J = 7.1, 5.0 Hz, 6H) ppm。   

  ¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.86 (d, J = 4.7 Hz, 1H), 7.74 (t, J = 1.6 Hz, 1H), 7.70 (t, J = 1.7 Hz, 1H), 7.67 (t, J = 1.8 Hz, 1H), 7.49 (d, J = 1.9 Hz, 2H), 7.43 (t, J = 1.8 Hz, 1H), 7.38 (d, J = 4.7 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.27-7.19 (m, 1H), 7.02-6.84 (m, 2H), 6.25 (d, J = 7.5 Hz, 1H), 5.38 (q, J = 5.8 Hz, 1H), 4.36 (ddd, J = 9.8, 6.2, 3.4 Hz, 1H), 4.23 (ddd, J = 11.6, 8.9, 2.9 Hz, 1H), 4.12 (p, J = 7.0 Hz, 1H), 2.48-2.32 (m, 1H), 2.31-2.17 (m, 1H), 1.63 (dd, J = 7.1, 3.2 Hz, 6H) ppm。

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.07 (d, J = 8.4 Hz, 1H), 8.98 (d, J = 2.1 Hz, 1H), 8.87 (d, J = 4.8 Hz, 1H), 8.76 (dd, J = 4.8, 3.3 Hz, 1H), 8.23-8.19 (m, 1H), 7.67-7.62 (m, 2H), 7.24-7.14 (m, 2H), 6.91 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.30-5.23 (m, 1H), 4.26 (s, 2H), 3.98-3.91 (m, 1H), 2.18-2.04 (m, 2H), 1.54-1.50 (m, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.09 (d, J = 8.4 Hz, 1H), 8.89 (d, J = 4.8 Hz, 1H), 8.82 (d, J = 4.5 Hz, 2H), 7.80 (d, J = 4.5 Hz, 2H), 7.65 (d, J = 4.8 Hz, 1H), 7.25-7.14 (m, 2H), 6.91 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.30-5.23 (m, 1H), 4.26 (s, 2H), 3.97-3.86 (m, 1H), 2.22-2.03 (m, 2H), 1.53-1.50 (m, 6H) ppm。   

1H-NMR (300 MHz, DMSO-d6)：δ = 9.01 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 4.8 Hz, 1H), 7.25 (d, J = 4.5 Hz, 1H), 7.15 (t, J = 6.8 Hz, 1H), 5.25-5.15 (m, 1H), 4.25-4.35 (m, 2H), 3.75-3.85 (m, 3H), 2.51 (s, 2H), 2.05-2.20 (m, 2H), 1.90-1.75 (m, 3H), 1.55 (t, J = 4.5 Hz, 6H), 1.40 (t, J = 4.5 Hz, 6H), 1.80 (dd, J = 4.5 Hz, J = 4.2 Hz, 1H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.70 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.18 (d, J = 4.5 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.26 (d, J = 6.9 Hz, 1H), 5.40-5.38 (m, 1H), 4.37-4.34 (m, 1H), 4.29-4.25 (m, 1H), 4.11-4.07 (m, 1H), 3.10-3.07 (m, 1H), 2.40-2.36 (m, 1H), 2.29-2.26 (m, 1H), 1.80-1.75 (m, 1H), 1.60 (dd, J = 6.9, 3.0 Hz, 6H), 1.56-1.49 (m, 2H), 1.35 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 5.7 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.05 (d, J = 8.4 Hz, 1H), 8.65 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 4.8 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.81(d, J = 8.1 Hz, 1H), 5.31-5.24 (m, 1H), 4.33-4.23 (m, 2H), 3.90-3.81 (m, 1H), 3.27-3.22 (m, 1H), 2.18-2.02 (m, 4H), 1.84-1.75 (m, 6H), 1.50-1.46 (m, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 8.65 (d, J = 8.4 Hz, 1H), 7.35-7.25 (m, 2H), 7.21-7.16 (m, 1H), 6.90-6.85 (m, 1H), 6.81 (d, J = 8.1 Hz, 1H), 5.35-5.29 (m, 1H), 4.33-4.23 (m, 2H), 3.90-3.81 (m, 1H), 3.90-2.75 (m, 1H), 2.35-2.05 (m, 2H), 2.01-1.80 (m, 5H), 1.80-1.3 (m, 11H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.69 (d, J = 4.7 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 19.3, 6.3 Hz, 2H), 7.02-6.81 (m, 2H), 6.23 (d, J = 7.5 Hz, 1H), 5.35 (q, J = 6.1 Hz, 1H), 4.44-4.29 (m, 1H), 4.22 (t, J = 9.9 Hz, 1H), 4.06 (p, J = 7.3 Hz, 1H), 2.83 (s, 1H), 2.48-2.16 (m, 4H), 2.15-1.77 (m, 7H), 1.57 (dd, J = 7.4, 3.2 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d ₆ )：δ = 9.04 (d, J = 8.3 Hz, 1H), 8.69 (d, J = 4.8 Hz, 1H), 7.36 (d, J = 4.8 Hz, 1H), 7.30-7.13 (m, 2H), 7.00-6.88 (m, 1H), 6.87-6.76 (m, 1H), 6.50-6.42 (m, 1H), 5.34-5.20 (m, 1H), 4.34-4.20 (m, 2H), 3.98-3.78 (m, 1H), 2.64-2.53 (m, 2H), 2.23-2.00 (m, 4H), 1.63-1.53 (m, 2H), 1.53-1.43 (m, 6H), 0.45-0.35 (m, 4H) ppm。   

¹ H-NMR (300 MHz, DMSO-d ₆ )：δ = 9.05 (d, J = 8.2 Hz, 1H), 8.66 (d, J = 4.8 Hz, 1H), 7.46-7.12 (m, 3H), 7.03-6.87 (m, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.27 (d, J = 6.4 Hz, 1H), 4.27 (s, 2H), 3.99-3.76 (m, 1H), 2.92-2.71 (m, 1H), 2.30-2.04 (m, 2H), 2.02-1.68 (m, 6H), 1.48 (s, 6H), 0.99 (d, J = 12.6 Hz, 2H), 0.31 (d, J = 14.6 Hz, 4H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 7.26 (dt, J = 17.8, 7.8 Hz, 2H), 7.12 (s, 1H), 7.02-6.82 (m, 2H), 6.44 (s, 1H), 6.24 (s, 1H), 5.36 (s, 1H), 4.34 (q, J = 6.3, 4.5 Hz, 1H), 4.22 (t, J = 9.6 Hz, 1H), 4.07 (q, J = 7.3 Hz, 1H), 3.39 (s, 2H), 2.92 (s, 2H), 2.72 (s, 2H), 2.30 (d, J = 33.9 Hz, 2H), 1.57 (s, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 7.30 (d, J = 7.6 Hz, 1H), 7.25-7.15 (m, 2H), 7.03-6.76 (m, 2H), 6.21 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 6.6 Hz, 1H), 4.44-4.29 (m, 1H), 4.22 (dd, J = 11.2, 8.2 Hz, 1H), 4.04 (p, J = 7.0 Hz, 1H), 3.33-3.11 (m, 4H), 3.00 (t, J = 12.2 Hz, 1H), 2.55 (s, 2H), 2.45-2.15 (m, 4H), 1.56 (d, J = 7.1 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.81 (dd, J = 5.0, 1.6 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 7.72-7.49 (m, 2H), 7.34 (dd, J = 4.7, 1.7 Hz, 1H), 7.26 (d, J = 1.7 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.00-6.79 (m, 2H), 5.30 (q, J = 6.0 Hz, 1H), 4.41-4.28 (m, 1H), 4.20 (dd, J = 11.4, 8.0 Hz, 1H), 2.42-2.17 (m, 2H), 2.01 (dd, J = 24.1, 4.8 Hz, 6H) ppm。

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.82 (d, J = 4.8 Hz, 1H), 8.59 (d, J = 5.1 Hz, 1H), 7.62 (d, J = 1.3 Hz, 1H), 7.54 (dd, J = 5.1, 1.6 Hz, 1H), 7.37 (d, J = 4.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 7.4 Hz, 1H), 5.31 (d, J = 7.1 Hz, 1H), 4.40-4.29 (m, 1H), 4.26-4.13 (m, 1H), 2.34 (dd, J = 9.8, 4.5 Hz, 1H), 2.27-2.13 (m, 1H), 1.88 (d, J = 3.9 Hz, 5H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 10.59 (d, J = 4.0 Hz, 1H), 8.56 (d, J = 5.4 Hz, 1H), 7.26-7.22 (m, 2H), 6.95-6.88 (m, 2H), 6.76 (d, J = 5.4 Hz, 1H), 5.31-5.28 (m, 1H), 4.39-4.11 (m, 2H), 3.80-3.67 (m, 4H), 3.45-3.37 (m, 8H), 2.40-2.20 (m, 6H) ppm。   

1H-NMR (300 MHz, DMSO-d6)：δ = 10.56 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 4.4 Hz, 1H), 7.25-7.19 (m, 1H), 7.00-6.81 (m, 3H), 5.15 (m, 1H), 4.35-4.25 (m, 1H), 4.15-4.10 (m, 1H), 3.92-3.85 (m, 2H), 3.45-3.10 (m, 6H), 2.55-2.50 (b, 2H), 2.25-2.15 (m, 2H), 1.90-1.75 (m, 3H), 1.90 (d, J = 4.5 Hz, 6H), 1.85 (dd, J = 4.4 Hz, J = 4.1 Hz, 1H) ppm。   

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 8.99 (d, J = 8.1 Hz, 1H), 8.86 (d, J = 5.4 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.18 (t, J = 6.6 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 5.4 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.29-5.23 (m, 1H), 4.32-4.22 (m, 2H), 3.89-3.80 (m, 1H), 3.38 (d, J = 4.8 Hz, 4H), 2.17-2.06 (m, 2H), 1.68 (s, 6H), 1.41-1.49 (m, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.38 (d, J = 5.4 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.34 (d, J = 5.1 Hz, 1H), 6.23 (d, J = 6.3 Hz, 1H), 5.36-5.32 (m, 1H), 4.85 (s, 1H), 4.73 (s, 1H), 4.38-4.31 (m, 1H), 4.24-4.17 (m, 1H), 4.07-3.92 (m, 3H), 3.84 (d, J = 9.3 Hz, 1H), 3.66 (d, J = 8.7 Hz, 1H), 2.39-2.31 (m, 1H), 2.25-2.20 (m, 1H), 2.07 (s, 2H), 1.54 (dd, J = 6.6, 4.8 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.38 (d, J = 5.7 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 6.9 Hz, 1H), 6.99 (td, J = 7.2, 1.2 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 5.7 Hz, 1H), 6.24 (d, J = 6.3 Hz, 1H), 5.38-5.36 (m, 1H), 4.75 (d, J = 6.3 Hz, 2H), 4.69 (d, J = 6.3 Hz, 2H), 4.37-4.34 (m, 1H), 4.28-4.24 (m, 1H), 4.08-4.01 (m, 3H), 3.79-3.75 (m, 2H), 2.42-2.36 (m, 3H), 2.29-2.26 (m, 1H), 1.56 (dd, J = 6.9, 3.9 Hz, 6H) ppm。   

¹ H-NMR: (300 MHz, DMSO-d₆ )：δ = 9.62 (d, J = 8.1 Hz, 1H), 8.97 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 4.8 Hz, 1H), 7.67-7.50 (m, 3H), 7.25 (d, J = 7.5 Hz, 1H), 7.22-7.13 (td, J = 7.5, 1.2 Hz, 1H), 6.93 (td, J = 7.5, 1.2 Hz, 1H), 6.81 (dd, J = 8.1, 1.2 Hz, 1H), 5.23 (q, J = 6.0 Hz, 1H), 4.24 (m, 2H), 2.19 (m, 1H), 2.07-2.00 (m, 1H) ppm。

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.52 (d, J = 8.1 Hz, 1H), 8.96 (d, J = 4.8 Hz, 1H), 7.75 (d, J = 4.8 Hz, 1H), 7.62 (m, 3H), 7.26-7.15 (m, 2H), 6.92 (td, J = 7.5 Hz, 0.9 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 5.22 (d, J = 7.8 Hz, 1H), 4.27-4.18 (m, 2H), 2.19-2.16 (m, 1H), 2.08-1.98 (m, 1H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.70 (d, J = 4.5 Hz, 1H), 7.32 (d, J = 6.6 Hz, 1H), 7.24-7.21 (m, 1H), 7.16 (d, J = 4.8 Hz, 1H), 6.99-6.94 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.22 (d, J = 6.6 Hz, 1H), 5.37-5.35 (m, 1H), 4.35-4.32 (m, 1H), 4.26-4.16 (m, 1H), 4.12-4.05 (m, 3H), 3.63-3.56 (m, 2H), 3.01-2.96 (m, 1H), 2.38-2.35 (m, 1H), 2.26-2.23 (m, 1H), 2.03-1.87 (m, 4H) , 1.59-1.54 (m, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.71 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.26-7.21 (m, 1H), 7.16 (d, J = 4.8 Hz, 1H), 6.98-6.93 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.46 (s, 1H), 6.22 (d, J = 7.2 Hz, 1H), 5.38-5.35 (m, 1H), 4.40-4.31 (m, 3H), 4.26-4.18 (m, 1H), 4.10-4.06 (m, 1H), 3.98 (t, J = 5.4 Hz, 2H), 2.60-2.58 (m, 2H), 2.38-2.31 (m, 1H), 2.28-2.22 (m, 1H), 1.59-1.52 (m, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.70 (d, J = 4.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 4.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.36 (s, 1H), 6.21 (d, J = 6.6 Hz, 1H), 5.41-5.34 (m, 1H), 4.36-4.31 (m, 1H), 4.26-4.22 (m, 1H), 4.19-4.06 (m, 1H), 2.58-2.33 (m, 6H), 2.27-2.19 (m, 2H), 1.86-1.72 (m, 1H), 1.57 (dd, J = 6.9, 3.0 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.69 (d, J = 4.8 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 5.7 Hz, 1H), 6.99 (t, J = 8.4 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.5 Hz, 1H), 5.37-5.34 (m, 1H), 4.35-4.32 (m, 1H), 4.26-4.22 (m, 1H), 4.08-4.04 (m, 1H), 2.89-2.87 (m, 1H), 2.40-2.27 (m, 2H), 2.26-2.13 (m, 1H), 2.12-2.06 (m, 2H), 2.01-1.79 (m, 6H), 1.57 (dd, J = 7.2, 3.3 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, CDCl₃ )：δ = 8.70 (d, J = 4.8 Hz, 1H), 7.32-7.22 (m, 2H), 7.14 (d, J = 4.8 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.21 (s, 2H), 5.35 (q, J = 5.9 Hz, 1H), 4.40- 4.33 (m, 1H), 4.58 - 4.20 (m, 1H), 4.14 - 4.05 (m, 1H), 2.90-2.69 (m, 4H), 2.43-2.14 (m, 4H), 1.58 (dd, J = 6.1, 3.0 Hz, 6H) ppm。   

¹ H-NMR (300 MHz, DMSO-d6)：δ = 9.12 (d, J = 8.1 Hz, 1H), 8.86 (d, J = 4.5 Hz, 1H), 7.62-7.46 (m, 4H), 7.06-7.00 (m, 2H), 6.85-6.80 (m, 1H), 5.27-5.24 (m, 1H), 4.26-4.23 (m, 2H), 3.97-3.92 (m, 1H), 2.14-2.04 (m, 2H), 1.51 (dd, J = 7.0, 4.7 Hz, 6H) ppm。

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.12 (d, J = 8.1 Hz, 1H), 8.89 (d, J = 4.8 Hz, 1H), 7.83-7.78 (m, 1H), 7.59 (d, J = 4.8 Hz, 1H), 7.54-7.50 (m, 1H), 7.06-6.99 (m, 2H), 6.84-6.80 (m, 1H), 5.25 (q, J = 6.6 Hz, 1H), 4.25-4.22 (m, 2H), 3.95-3.90 (m, 1H), 2.14-2.02 (m, 2H), 1.52 (dd, J = 6.9, 4.8 Hz, 6H) ppm。

¹ H-NMR (300 MHz, DMSO-d₆ )：δ = 9.10 (d, J = 8.4 Hz, 1H), 8.88 (d, J = 4.8 Hz, 1H), 7.82-7.78 (m, 1H), 7.57 (d, J = 4.5 Hz, 1H), 7.52-7.48 (m, 1H), 7.22-7.13 (m, 2H), 6.90 (td, J = 7.5, 1.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.25 (q, J = 6.6 Hz, 1H), 4.24-4.22 (m, 2H), 3.94-3.89 (m, 1H), 2.14-2.06 (m, 2H), 1.52 (dd, J = 7.0, 4.8 Hz, 6H) ppm。 The following other compounds were prepared according to the aforementioned procedure:

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.95 (d, J = 7.2 Hz, 1H), 7.83 (dd, J = 8.0, 1.2 Hz, 1H), 7.74 (d, J = 1.9 Hz, 2H ), 7.54 (dd, J = 7.6, 1.2 Hz, 1H), 7.44-7.34 (m, 2H), 7.28-7.21 (m, 2H), 7.02-6.89 (m, 2H), 5.40-5.27 (m, 1H) ), 4.47-4.32 (m, 1H), 4.29-4.15 (m, 1H), 3.69-3.48 (m, 4H), 3.42-3.24 (m, 4H), 2.47-2.18 (m, 2H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.88 (dd, J = 7.9, 1.2 Hz, 1H), 7.67 (d, J = 1.9 Hz, 2H), 7.50 (dd, J = 7.5, 1.2 Hz , 1H), 7.48-7.41 (m, 1H), 7.41-7.34 (m, 2H), 7.32-7.29 (m, 2H), 7.26 (d, J = 5.7 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.77-5.59 (m, 1H), 4.51-4.23 (m, 1H), 3.21- 2.86 (m, 2H), 2.85-2.68 (m, 1H), 2.07-1.86 (m, 1H), 1.53 (dd, J = 7.1, 2.8 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.93 (dd, J = 7.9, 1.3 Hz, 1H), 7.55-7.44 (m, 1H), 7.43-7.33 (m, 2H), 7.32 (d, J = 1.6 Hz, 1H), 7.26-7.17 (m, 1H), 7.07-6.97 (m, 2H), 6.97-6.90 (m, 1H), 6.87 (dd, J = 8.2, 1.2 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 5.49-5.27 (m, 1H), 4.46-4.11 (m, 3H), 2.36 (dddd, J = 16.3, 8.3, 5.4, 3.2 Hz, 1H), 2.14 (dtd , J = 14.0, 7.1, 3.1 Hz, 1H), 1.54 (dd, J = 7.1, 2.9 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.40 (s, 1H), 8.06 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 6.82(d, J = 8.4 Hz, 1H) , 5.39 (t, J =5.7 Hz, 1H), 4.34-4.29 (m, 2H), 3.66-3.61 (m, 1H), 2.33-2.26 (m, 2H), 1.43-1.39 (m, 6H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.40 (s, 1H), 8.06 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H) , 5.39 (t, J =5.7 Hz, 1H), 4.34-4.29 (m, 2H), 3.66-3.61 (m, 1H), 2.33-2.26 (m, 2H), 1.43-1.39 (m, 6H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.40 (s, 1H), 8.06 (s, 1H), 7.96(d, J = 8.7 Hz, 1H), 7.60(d, J = 8.7 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H) , 5.39 (t, J = 5.7 Hz, 1H), 4.34-4.29 (m, 2H), 3.66-3.61 (m, 1H), 2.33-2.26 (m, 2H), 1.43-1.39 (m, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d6): δ = 8.48 (d, J = 8.7 Hz, 2H), 7.87-7.79 (m, 2H), 7.62-7.56 (m,2H), 7.31-7.15 (m , 3H), 6.95-6.90 (m, 1H), 6.82-6.80 (m, 1H), 5.50 (s, 1H), 5.26-5.19 (m, 1H), 5.13 (s, 1H), 4.27-4.23 (m , 2H), 2.18-2.05 (m, 5H) ppm.

¹ H-NMR (300 MHz, DMSO-d6): δ = 9.04 (d, J = 8.4 Hz, 1H), 8.44 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.83-7.79 ( m, 1H), 7.58-7.55 (m, 2H), 7.29-7.15 (m, 3H), 6.96-6.90 (m, 1H), 6.81-6.78 (m, 1H), 5.28 (d, J = 7.5 Hz, 1H), 4.30-4.25 (m, 2H), 3.81-3.76 (m, 1H), 2.27-1.95 (m, 2 H), 1.47-1.43 (m, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d6): δ = 10.06 (d, J = 8.1 Hz, 1H), 8.45 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.2 Hz, 2H), 7.33-7.17 (m, 3H), 6.95-6.90 (m, 1H), 6.85 (d, J = 8.1 Hz, 1H), 5.26-5.20 (m, 1H), 4.36-4.30 (m, 1H), 4.24-4.19 (m, 1H), 2.90 (s, 6H), 2.28-2.23 (m, 1H), 2.13-2.08 (m, 1H) ) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 10.44 (s, 1H), 8.04 (dd, J = 8.0, 1.2 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.42 (dd , J = 7.3, 1.1 Hz, 1H), 7.28-7.18 (m, 4H), 7.04-6.80 (m, 3H), 5.29 (s, 1H), 4.50-4.29 (m, 1H), 4.22 (dt, J = 12.0, 6.4 Hz, 1H), 3.41 (d, J = 49.1 Hz, 8H), 2.45-2.24 (m, 2H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.22 (d, J = 8.1 Hz, 1H), 7.61-7.49 (m, 1H), 7.42 (dd, J = 7.3, 1.0 Hz, 1H), 7.24 (s, 1H), 7.20-7.17 (m, 2H), 7.09-7.77 (m, 3H), 6.23 (d, J = 7.4 Hz, 1H), 5.36 (q, J = 5.7 Hz, 2H), 4.36- 4.33 (m, 1H), 4.26-4.16 (m, 4H), 3.74-3.58 (m, 2H), 2.55 (q, J = 12.6 Hz, 2H), 2.45-2.32 (m, 1H), 2.31-2.13 ( m, 1H), 1.79 (d, J = 13.6 Hz, 3H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.66 (dd, J = 7.8, 1.5 Hz, 1H), 7.53-7.41 (m, 2H), 7.25-7.17 (m, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.98-6.82 (m, 3H), 5.97-5.96 (m, 1H), 5.32-5.29 (m, 1H), 4.37-4.30 (m, 1H), 4.21-3.96 (m, 3H), 3.81-3.74 (m, 1H), 3.68-3.61 (m, 1H), 2.49-2.27 (m, 3H), 2.26-2.14 (m, 1H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.68 (d, J = 5.7 Hz, 1H), 7.73-7.62 (m, 2H), 7.57 (d, J = 5.5 Hz, 1H), 7.29-7.18 (m, 3H), 7.03-6.87 (m, 3H), 5.60 (s, 1H), 5.59-5.37 (m, 1H), 5.25 (s, 1H), 4.36-4.33 (m, 1H), 4.21-4.13 (m, 1H), 2.40-2.37 (m, 1H), 2.23-2.15 (m, 4H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.71 (d, J = 5.1 Hz, 1H), 7.96 (d, J = 4.8 Hz, 1H), 7.59-7.57 (m, 2H), 7.31-7.23 (m, 2H), 7.02-6.98 (m, 2H), 6.96-6.89 (m, 1H), 6.29-6.27 (m, 1H), 5.39-5.37 (m, 1H), 4.41-4.35 (m, 1H) , 4.26-4.20 (m, 1H), 4.05-4.00 (m, 1H), 2.42-2.38 (m, 4H), 2.36-2.22 (m, 1H), 1.58-1.55 (m, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d6): δ = 9.87 (d, J = 8.0 Hz, 1H), 8.67 (d, J = 5.5 Hz, 1H), 8.08 (d, J = 5.5 Hz, 1H) , 7.74-7.63 (m, 2H), 7.55-7.44 (m, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.24-7.16 (m, 1H), 6.95-6.90 (m, 1H), 6.84 -6.82 (m, 1H), 5.27-5.25 (m, 1H), 4.32-4.22 (m, 2H), 2.92 (s, 6H), 2.27-2.22 (m, 1H), 2.14-2.08 (m, 1H) ppm.

¹ H-NMR (300 MHz, DMSO-d6): δ 10.20 (d, J = 7.1 Hz, 1H), 8.66 (d, J = 5.5 Hz, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7.69-7.66 (m, 2H), 7.51-7.47 (m, 1H), 7.36-7.34 (m, 1H), 7.28-7.23 (m, 1H), 6.97-6.87 (m, 2H), 5.18-5.16 (m , 1H), 4.32-4.31 (m, 1H), 4.21-4.18 (m, 1H), 3.47-3.38 (m, 4H), 3.36-3.25 (m, 4H), 2.69 (s, 2H), 2.22-2.08 (m, 2H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.99 (s, 1H), 8.57 (s, 1H), 7.50-7.38 (m, 2H), 7.34-7.25 (m, 1H), 7.25-7.10 (m, 2H), 6.95-6.91 (m, 1H), 6.83 (d, J = 8.3 Hz, 1H), 5.64 (t, J = 1.6 Hz, 1H), 5.30 (d, J = 2.5 Hz, 2H) , 4.29-4.24 (m, 2H), 2.38-2.09 (m, 5H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 9.30 (s, 1H), 8.52 (s, 1H), 7.40 (d, J = 6.5 Hz, 2H), 7.30 (d, J = 7.7 Hz, 1H), 7.16 (m, 2H), 6.94 (t, J = 7.4 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 5.33 (t, J = 5.6 Hz, 1H), 4.32-4.28 ( m, 2H), 3.94-3.81 (m, 1H), 2.28 (s, 1H), 1.58 (d, J = 7.1 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 9.36 (s, 1H), 8.54 (s, 1H), 7.42-7.38 (m, 2H), 7.35-7.29 (m, 1H), 7.28-7.11 (m, 2H), 6.97-6.64 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.38-4.34 (m, 1H), 4.27- 4.24 (m, 1H), 3.00 (s, 5H), 2.37-2.34 (m, 1H), 2.27-2.12 (m, 1H), 1.43-1.21 (m, 2H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 9.43 (s, 1H), 8.55 (s, 1H), 7.47-7.12 (m, 5H), 7.04-6.89 (m, 2H), 5.22 (t , J = 4.5 Hz, 1H), 4.43-4.32 (m, 1H), 4.32-4.17 (m, 1H), 3.57- 3.45 (m, 2H), 3.43-3.36 (m, 2H), 2.31-2.28 (m , 2H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD) δ = 8.88 (s, 1H), 8.05 (s, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.24-7.13 (m, 1H), 6.95 (td, J = 7.5, 1.2 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 5.34 (t, J = 5.7 Hz, 1H), 4.31-4.27 (m, 2H), 3.79 (p, J = 7.1 Hz, 1H), 3.59 (d, J = 11.6 Hz, 2H), 2.47-2.30 (m, 2H), 2.30-2.10 (m, 2H), 1.92 (d, J = 11.1 Hz, 3H), 1.53 (dd, J = 7.2, 2.0 Hz, 6H), 0.98 (dd, J = 6.4, 3.4 Hz, 6H), 0.95-0.71 (m, 2H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.96 (s, 1H), 8.18-8.12 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.25-7.13 (m, 1H) ), 6.99-6.95 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.34 (t, J = 5.7 Hz, 1H), 4.37-4.22 (m, 2H), 3.80 (p, J = 7.2 Hz, 1H), 3.41 (t, J = 5.7 Hz, 5H), 2.26-2.24 (m, 6H), 1.53 (d, J = 7.2 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.92 (d, J = 4.8 Hz, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.25-7. 23 (m, 1H), 7.02 -7.01 (m, 1H), 7.01-6.92 (m, 1H), 6.92-6.89 (m, 1H), 6.26 (d, J = 6.9 Hz, 1H), 5.40-5.37 (m, 1H), 4.37-4.34 (m, 1H), 4.28-4.21 (m, 1H), 4.11-4.07 (m, 1H), 2.41-2.37 (m, 1H), 2.29-2.25 (m, 1H), 1.61-1.54 (m, 6H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.80 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 4.8 Hz, 1H), 7.53-7.43 (m, 2H), 7.30 ( dd, J = 7.6, 1.2 Hz, 1H), 7.26-7.15 (m, 2H), 6.94 (td, J = 7.5, 1.2 Hz, 1H), 6.83 (dd, J = 8.3, 1.2 Hz, 1H), 5.52 (t, J = 1.7 Hz, 1H), 5.36-5.21 (m, 2H), 4.36-4.15 (m, 2H), 2.35-2.23 (m, 4H), 2.23-2.08 (m, 1H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.08 (d, J = 8.4 Hz, 1H), 8.86 (d, J = 4.8 Hz, 1H), 7.61-7.46 (m, 4H), 7.24 -7.14 (m, 2H), 6.94-6.89 (m, 1H), 6.80 (d, J = 8.1, 1H), 5.27 (q, J = 7.1 Hz, 1H), 4.36-4.07 (m, 2H), 3.96 -3.91 (m, 1H), 2.28-2.04 (m, 2H), 1.52 (dd, J = 7.0, 4.7 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.82 (d, J = 4.7 Hz, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.50-7.38 (m, 2H), 7.38- 7.14 (m, 3H), 7.04-6.89 (m, 2H), 5.22 (t, J = 4.4 Hz, 1H), 4.45-4.32 (m, 1H), 4.30-4.19 (m, 1H), 3.61-3.39 ( m, 6H), 3.39-3.34 (m, 2H), 2.31 (p, J = 4.2 Hz, 2H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.84 (d, J = 4.7 Hz, 1H), 7.61-7.48 (m, 2H), 7.47-7.16 (m, 8H), 7.02-6.85 (m, 2H), 6.24 (d, J = 7.6 Hz, 1H), 5.37 (q, J = 5.9 Hz, 1H), 4.42-4.06 (m, 3H), 2.45-2.18 (m, 2H), 1.65-1.62 (m , 6H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.76 (d, J = 4.8 Hz, 1H), 7.89-7.78 (m, 2H), 7.45 (d, J = 4.8 Hz, 1H), 7.33- 7.28 (m, 3H), 7.17 (td, J = 7.9, 1.7 Hz, 1H), 6.93 (td, J = 7.5, 1.2 Hz, 1H), 6.81 (dd, J = 8.2, 1.3 Hz, 1H), 5.33 (t, J = 5.7 Hz, 1H), 4.35-4.24 (m, 2H), 3.88 (p, J = 7.1 Hz, 1H), 2.38-2.08 (m, 2H), 1.58 (dd, J = 7.1, 2.5 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.81 (d, J = 4.7 Hz, 1H), 7.43-7.30 (m, 3H), 7.29 (d, J = 7.6 Hz, 1H), 7.20- 7.12 (m, 2H), 6.96-6.91 (m, 1H), 6.81 (dd, J = 8.3, 1.2 Hz, 1H), 5.28 (t, J = 5.2 Hz, 1H), 4.33-7.24 (m, 2H) , 2.30-2.13 (m, 2H), 1.70 (s, 9H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.79 (d, J = 4.8 Hz, 1H), 7.56 (dd, J = 11.1, 1.8 Hz, 3H), 7.37-7.29 (m, 2H), 7.29 -7.18 (m, 3H), 6.99-6.96 (m, 1H), 6.88 (dd, J = 8.3, 1.2 Hz, 1H), 6.60 (d, J = 7.5 Hz, 1H), 5.33 (q, J = 5.8 Hz, 1H), 4.39-4.33 (m, 1H), 4.25-4.20 (m, 1H), 2.46-2.17 (m, 2H), 1.89 (d, J = 4.2 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.79 (d, J = 4.8 Hz, 1H), 7.56 (d, J = 11.1 Hz, 3H), 7.37-7.29 (m, 2H), 7.29-7.18 (m, 3H), 6.97 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 8.3, 1.2 Hz, 1H), 6.60 (d, J = 7.4 Hz, 1H), 5.33 (q, J = 5.7 Hz, 1H), 4.42-4.29 (m, 1H), 4.25-4.20 (m, 1H), 2.46-2.18 (m, 2H), 1.89 (d, J = 4.2 Hz, 6H), 1.28 (s, 1H) ), 1.08 (d, J = 1.3 Hz, 1H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.82 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 1.9 Hz, 2H), 7.66 (t, J = 1.9 Hz, 1H) , 7.50 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 9.1 Hz, 1H), 6.99-6.87 (m, 1H), 6.81 (d, J = 9.0 Hz, 1H), 5.34 (t, J = 6.1 Hz, 1H), 4.28 (t, J = 5.4 Hz, 2H), 3.94-3.91 (m, 1H), 2.37-2.09 (m, 3H), 1.58 (d, J = 7.1 Hz, 6H) ppm .

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.92 (d, J = 7.2 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 7.61-7.46 (m, 4H), 7.40 (d, J = 4.8 Hz, 1H), 6.91 (d, J = 4.8 Hz, 1H), 5.36 (d, J = 6.6 Hz, 1H), 3.91 (t, J = 7.2 Hz, 1H), 3.05-2.91 (m, 1H), 2.90-2.82 (m, 2H), 2.40-2.34 (m, 1H), 1.50 (dd, J =1.8, 3.0 Hz, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.92 (d, J = 7.8 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 7.61-7.46 (m, 4H), 7.40 (d, J = 4.8 Hz, 1H), 6.91 (d, J = 5.1 Hz, 1H), 5.36 (d, J = 6.0 Hz, 1H), 3.91 (t, J = 6.9 Hz, 1H), 3.05-2.98 (m, 1H), 2.90-2.82 (m, 2H), 2.40-2.34 (m, 1H), 1.50 (dd, J =2.1, 2.1 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.85 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 4.8 Hz, 1H), 729-7.25 (m, 2H), 7.01-6.95 (m, 1H), 6.86 (s, 1H), 6.12 (d, J = 7.8 Hz, 1H), 5.53 (d, J = 4.8 Hz, 1H), 4.15-4.06 (m, 1H). 3.08-2.93 ( m, 3H), 2.35-2.25 (m, 1H), 1.61 (d, J = 6.9 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.85 (d, J = 4.5 Hz, 1H), 7.35-7.26 (m, 3H), 7.01-6.93 (m, 1H), 6.86 (s, 1H) , 6.12 (d, J = 8.1 Hz, 1H), 5.53 (d, J = 5.7 Hz, 1H), 4.15-4.06 (m, 1H). 3.11-2.93 (m, 3H), 2.35-2.25 (m, 1H) ), 1.61 (d, J = 6.6 Hz, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d6): δ = 9.01 (d, J = 7.8 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 7.61-7.49 (m, 5H), 5.37 ( t, J = 6.3 Hz, 1H), 3.92 (t, J = 6.6 Hz, 1H), 3.14-2.83 (m, 3H), 2.50-2.32 (m, 1H), 1.48 (d, J = 7.2 Hz, 6H ) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.92 (d, J = 4.7 Hz, 1H), 7.81 (d, J = 1.9 Hz, 2H), 7.73-7.64 (m, 1H), 7.59 ( dd, J = 11.8, 4.9 Hz, 1H), 7.13 (dd, J = 9.0, 3.1 Hz, 1H), 6.97-6.74 (m, 1H), 6.82 (dd, J = 9.1, 4.7 Hz, 1H), 5.29 (t, J = 5.8 Hz, 1H), 4.29-4.24 (m, 2H), 2.93 (s, 2H), 2.26-2.21 (m, 2H), 2.05 (d, J = 5.8 Hz, 1H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.82 (d, J = 4.9 Hz, 1H), 7.78 (d, J = 1.9 Hz, 2H), 7.68 (t, J = 1.9 Hz, 1H) , 7.54 (d, J = 4.9 Hz, 1H), 7.18-7.08 (m, 1H), 6.96-6.92 (m, 1H), 6.80 (dd, J = 9.0, 4.8 Hz, 1H), 5.27 (t, J = 5.6 Hz, 1H), 4.36-4.12 (m, 2H), 2.35-2.09 (m, 2H), 1.86 (d, J = 3.2 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.83 (d, J = 4.8 Hz, 1H), 7.77 (d, J = 1.9 Hz, 2H), 7.67 (t, J = 1.9 Hz, 1H) , 7.50 (d, J = 4.8 Hz, 1H), 7.12 (d, J = 9.2Hz, 1H), 6.94-6.90 (m, 1H), 6.79 (d, J = 9.0 Hz, 1H), 5.27 (t, J = 5.8 Hz, 1H), 4.34-4.18 (m, 2H), 2.01 (d, J = 23.5Hz, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.85 (d, J = 4.8 Hz, 1H), 7.66 (d, J = 1.9 Hz, 2H), 7.55 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 5.7 Hz, 1H), 7.36 (d, J = 4.7 Hz, 1H), 7.28-7.24 (m, 3H), 7.01-6.86 (m, 2H), 5.63-5.56 (m, 1H) , 5.39-5.36 (m, 1H), 5.31-5.24 (m, 1H), 4.38-4.34 (m, 1H), 4.19-4.16 (m, 1H), 2.48-2.31 (m, 1H), 2.27-2.11 ( m, 4H) ppm.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ = 9.52 (d, J = 8.0 Hz, 1H), 8.90 (d, J = 1.7 Hz, 1H), 7.91-7.79 (m, 3H), 7.36 -7.11 (m, 2H), 6.95-6.75 (m, 2H), 5.89 (s, 1H), 5.17 (t, J = 6.7 Hz, 1H), 4.34-4.14 (m, 2H), 2.16-2.00 (m , 2H), 1.76 (d, J = 3.1 Hz, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.08 (d, J = 8.2 Hz, 1H), 8.93 (d, J = 1.8 Hz, 1H), 7.90 (t, J = 1.9 Hz, 1H ), 7.85-7.80 (m, 2H), 7.30-7.22 (m, 1H), 7.21-7.12 (m, 1H), 6.96-6.84 (m, 1H), 6.82-6.74 (m, 1H), 5.16 (q , J = 6.2 Hz, 1H), 4.21 (d, J = 8.4 Hz, 2H), 2.10 (s, 2H), 1.98-1.86 (m, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.08 (d, J = 8.2 Hz, 1H), 8.91 (d, J = 1.8 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H ), 7.81 (dd, J = 2.0, 0.8 Hz, 2H), 7.25-7.11 (m, 2H), 6.90 (t, J = 7.4, 1H), 6.79 (dd, J = 8.2, 1.2 Hz, 1H), 5.24 (q, J = 6.8 Hz, 1H), 4.25 (q, J = 5.3, 4.5 Hz, 2H), 4.00-3.84 (m, 1H), 2.19-1.99 (m, 2H), 1.50 (dd, J = 7.0, 4.7 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.63 (s, 1H), 8.40 (s, 1H), 7.54 (d, J = 6.4 Hz, 3H), 7.37 (t, J = 7.6 Hz, 1H ), 7.23 (d, J = 7.5 Hz, 1H), 7.13-6.98 (m, 2H), 4.39 (d, J = 11.3 Hz, 1H), 4.10-3.92 (m, 2H), 3.87-3.70 (m, 1H), 2.67-2.56 (m, 1H), 2.34 (d, J = 13.6 Hz, 1H), 1.11 (d, J = 5.6 Hz, 3H), 1.01 (d, J = 5.6 Hz, 3H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.36 (d, J = 8.1 Hz, 1H), 8.90 (d, J = 1.6 Hz, 1H), 7.88 (t, J = 1.9 Hz, 1H ), 7.79 (d, J = 2.0 Hz, 2H), 7.26-7.11 (m, 2H), 6.90 (t, J = 7.5, 1H), 6.79 (dd, J = 8.2, 1.2 Hz, 1H), 5.18 ( q, J = 5.9 Hz, 1H), 4.32-4.14 (m, 2H), 2.20-2.10 (m, 1H), 2.03-1.93 (m, 1H), 1.60 (s, 9H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.39 (d, J = 8.0 Hz, 1H), 8.91 (d, J = 1.6 Hz, 1H), 7.88 (t, J = 1.9 Hz, 1H ), 7.79 (dd, J = 1.9, 0.9 Hz, 2H), 7.09-6.96 (m, 2H), 6.87-6.76 (m, 1H), 5.24-5.12 (m, 1H), 4.29-4.13 (m, 2H) ), 2.18-2.09 (m, 1H), 2.00 (d, J = 2.9 Hz, 1H), 1.60 (s, 9H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.06 (d, J = 8.3 Hz, 1H), 8.91 (d, J = 1.9 Hz, 1H), 7.51 (dd, J = 7.1, 3.0 Hz , 3H), 7.25-7.12 (m, 2H), 6.90 (t, J = 7.5, 1H), 6.79 (dd, J = 8.2, 1.2 Hz, 1H), 5.24 (q, J = 6.7 Hz, 1H), 4.33-4.16 (m, 2H), 4.00-3.85 (m, 1H), 2.19-2.01 (m, 2H), 1.55-1.46 (m, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.83 (d, J = 4.8 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.37-7.26 (m, 2H), 7.00-6.90 (m, 3H), 6.856.80 (m, 1H), 5.61 (s, 1H), 5.36 (t, J = 6.6 Hz, 1H ), 5.27 (s, 1H), 4.33-4.27 (m, 1H), 4.18-4.11 (m, 1H), 2.38-2.31 (m, 1H), 2.24 (s, 3H), 2.14-2.09 (m, 1H), 1.52 (d, J = 8.7 Hz, 1H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.85 (d, J = 4.5 Hz, 1H), 8.76 (d, J = 9.3 Hz, 1H), 7.60-7.46 (m, 4H), 7.40 (d, J = 5.1 Hz, 1H), 6.91 (d, J = 5.1 Hz, 1H), 5.04 (d, J = 9.0 Hz, 1H), 3.88 (t, J = 6.9 Hz, 1H), 2.86 (d , J = 15.3 Hz, 1H), 2.66 (d, J = 15.3 Hz, 1H), 1.50 (d, J = 6.9 Hz, 6H), 1.28 (s, 3H), 1.14 (s, 3H) ppm.

¹ H-NMR (300 MHz, DMSO-d6): δ = 8.84 (d, J = 4.8 Hz, 1H), 8.76 (d, J = 9.3 Hz, 1H), 7.60-7.46 (m, 4H), 7.40 ( d, J = 5.1 Hz, 1H), 6.90 (d, J = 4.8 Hz, 1H), 5.03 (d, J = 9.0 Hz, 1H), 3.87 (t, J = 6.9 Hz, 1H), 2.86 (d, J = 15.3 Hz, 1H), 2.65 (d, J = 15.3 Hz, 1H), 1.50 (d, J = 6.9 Hz, 6H), 1.28 (s, 3H), 1.14 (s, 3H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.09 (d, J = 8.1 Hz, 1H), 8.92 (d, J = 1.8 Hz, 1H), 7.59-7.48 (m, 3H), 7.09 -6.95 (m, 2H), 6.88-6.78 (m, 1H), 5.23 (q, J = 6.7 Hz, 1H), 4.30-4.15 (m, 2H), 4.03-3.86 (m, 1H), 2.20-2.00 (m, 2H), 1.58-1.40 (m, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.10 (d, J = 8.2 Hz, 1H), 9.00-8.86 (m, 1H), 7.52 (d, J = 7.4 Hz, 3H), 7.14 -6.94 (m, 2H), 6.80 (dd, J = 9.1, 4.8 Hz, 1H), 5.16 (d, J = 6.3 Hz, 1H), 4.21 (s, 2H), 2.10 (s, 1H), 1.93 ( dd, J = 23.2, 7.3 Hz, 7H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.71 (d, J = 4.8 Hz, 1H), 7.36-7.29 (m, 1H), 7.26-7. 23(m, 1H), 7.02-6.96 ( m, 1H), 6.92-6.90 (m, 1H), 6.27 (d, J = 7.8 Hz, 1H), 5.00 (d, J = 6.9 Hz, 1H), 4.38-4.34 (m, 1H), 4.29-4.25 (m, 1H), 4.14-4.09 (m, 1H), 2.41-2.36 (m, 1H), 2.31-2.27 (m, 1H), 1.61-1.56 (m, 6H), 1.55 (s, 9H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.39 (d, J = 8.0 Hz, 1H), 8.91 (d, J = 1.6 Hz, 1H), 7.59-7.43 (m, 3H), 7.11 -6.98 (m, 2H), 6.88-6.78 (m, 1H), 5.17 (d, J = 7.3 Hz, 1H), 4.31-4.13 (m, 2H), 2.22-2.07 (m, 1H), 2.05-1.91 (m, 1H), 1.60 (s, 9H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.78 (s, 1H), 7.26-7.17 (m, 2H), 7.06-6.83 (m, 5H), 6.14 (d, J = 7.5 Hz, 1H) , 5.31 (q, J = 5.9 Hz, 1H), 4.35-4.28 (m, 1H), 4.21-4.13 (m, 1H), 4.08-3.99 (m, 1H), 2.42-2.27 (m, 1H), 2.23 -2.15 (m, 1H), 1.57 (dd, J = 7.1, 2.6 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 10.50 (d, J = 7.7 Hz, 1H), 8.80 (d, J = 4.7 Hz, 1H), 7.40-7.28 (m, 5H), 7.26-7.21 (m, 2H), 7.05-6.86 (m, 3H), 6.50-6.33 (m, 1H), 5.40 (q, J = 6.4 Hz, 1H), 4.38-4.34 (m, 1H), 4.30-4.27 (m , 1H), 3.03 (s, 6H), 2.51-2.35 (m, 1H), 2.23-2.20 (m, 1H), 1.41-1.16 (m, 1H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.63 (d, J = 4.8 Hz, 1H), 7.38-7.27 (m, 2H), 7.27-7.16 (m, 1H), 6.96-6.93 (m , 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.43-4.30 (m, 1H), 4.27-4.22 (m, 1H), 2.98 (s, 6H), 2.96-2.83 (m, 1H), 2.39-2.32 (m, 1H), 2.21-2.17 (m, 1H), 2.05 (s, 1H), 2.00 (s, 3H), 1.93 (s, 1H) , 1.86 (d, J = 12.5 Hz, 1H), 1.77-1.56 (m, 3H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.66 (d, J = 4.8 Hz, 1H), 7.38-7.29 (m, 2H), 7.28-7.16 (m, 1H), 6.97-6.91 (m , 1H), 6.86 (d, J = 8.2 Hz, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.39-4.35 (m, 1H), 4.28-4.23 (m, 1H), 3.09 (d, J = 9.3 Hz, 1H), 2.99 (s, 6H), 2.56-2.50 (m, 1H), 2.45-2.28 (m, 1H), 2.27-1.95 (m, 8H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.66 (d, J = 4.8 Hz, 1H), 7.38-7.29 (m, 2H), 7.28-7.16 (m, 1H), 6.97-6.92(M , 1H), 6.86 (dd, J = 8.2, 1.2 Hz, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.38-4.33 (m, 1H), 4.27-4.23 (m, 1H), 2.98 ( s, 7H), 2.45-2.28 (m, 2H), 2.27-2.11 (m, 5H), 1.74-1.62 (m, 4H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 7.89-7.77 (m, 3H), 7.70 (t, J = 1.9 Hz, 1H), 7.35-7.26 (m, 1H), 7.24-7.12 (m , 1H), 6.94 (td, J = 7.5, 1.3 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.34 (t, J = 5.6 Hz, 1H), 4.37-4.20 (m, 2H) , 3.88 (p, J = 7.0 Hz, 1H), 2.39-2.11 (m, 2H), 2.05 (s, 2H), 1.59 (d, J = 7.1 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.42 (d, J = 5.5 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.27-7.15 (m, 1H), 6.96- 6.93 (m, 1H), 6.88-6.78 (m, 2H), 5.29 (t, J = 5.6 Hz, 1H), 4.38-4.32 (m, 1H), 4.27-4.22 (m, 1H), 3.98 (d, J = 12.2 Hz, 2H), 2.95 (s, 6H), 2.52 (t, J = 11.9 Hz, 2H), 2.44-2.28 (m, 1H), 2.19-2.16 (m, 1H), 1.31 (s, 2H) ), 1.01 (d, J = 6.4 Hz, 6H), 0.94-0.79 (m, 2H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 8.43 (d, J = 5.5 Hz, 1H), 7.33 (d, J = 7.6, 1.6 Hz, 1H), 7.27-7.16 (m, 1H), 6.96-6.92 (m, 1H), 6.89-6.80 (m, 2H), 5.29 (t, J = 5.6 Hz, 1H), 4.38-4.32 (m, 1H), 4.26-4.24 (m, 1H), 3.49 ( t, J = 5.1 Hz, 4H), 2.95 (s, 6H), 2.44-2.28 (m, 1H), 2.26-2.10 (m, 1H), 1.82 (s, 2H), 1.80 (s, 3H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.93 (d, J = 8.4 Hz, 1H), 8.55 (s, 1H), 7.24-7.15 (m, 2H), 6.92 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 5.24 (m, 1H), 4.29-4.24 (m, 2H), 3.99 (s, 3H), 3.89-3.84 (m, 1H), 3.40-3.23 (m, 4H), 2.16-2.05 (m, 6H), 1.48-1.45 (m, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.20 (d, J = 7.8 Hz, 1H), 7.84-7.82 (m, 2H), 7.72-7.66 (m, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 5.50 (s, 1H) , 5.30-5.25 (m, 2H), 4.30-4.22 (m, 2H), 2.29 (s, 3H), 2.19-2.17 (m, 1H), 2.07-2.00 (m, 1H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.46 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 7.8 Hz, 2H), 7.79-7.65 (m, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.22-7.17 (m, 1H), 6.94 (t, J = 7.2 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 5.30 (q, J = 6.6 Hz, 1H), 4.27 (t, J = 4.8 Hz, 2H), 3.89-3.80 (m, 1H), 2.22-2.02 (m, 2H), 1.51 (dd, J = 7.0, 5.0 Hz, 6H) ppm .

¹ H-NMR (300 MHz, CD ₃ OD): δ = 9.33 (s, 1H), 7.59-7.56 (m, 2H), 7.32-7.18 (m, 3H), 6.95 (t, J = 7.5 Hz, 1H ), 6.83 (d, J = 8.1 Hz, 1H), 5.83 (s, 1H), 5.38 (s, 1H), 5.30 (t, J = 5.1 Hz, 1H), 4.32-4.23 (m, 2H), 2.37 (s, 3H), 2.31-2.21 (m, 2H), 2.20-2.15 (m, 1H) ppm.

¹ H-NMR (300 MHz, CD ₃ OD): δ = 9.29 (s, 1H), 7.57-7.54 (m, 2H), 7.33-7.16 (m, 3H), 6.98-6.93 (m, 1H), 6.83 (dd, J = 8.1, 0.9 Hz, 1H), 5.36 (t, J = 5.4 Hz, 1H), 4.33-4.27 (m, 2H), 4.00-3.95 (m, 1H), 2.34-2.30 (m, 1H) ), 2.22-2.16 (m, 1H), 1.65 (dd, J = 6.9, 3.0 Hz, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.11 (d, J = 8.4 Hz, 1H), 8.90 (d, J = 4.5 Hz, 1H), 7.80-7.74 (m, 1H), 7.62 (d, J = 4.5 Hz, 1H), 7.46-7.40 (m, 1H), 7.22-7.13 (m, 2H), 6.90 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 5.27-5.21 (m, 1H), 4.24 (t, J = 5.1 Hz, 2H), 3.99-3.85 (m, 1H), 2.18-2.00 (m, 2H), 1.54-1.50 (m, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.05 (d, J = 8.4 Hz, 1H), 8.87 (d, J = 4.8 Hz, 1H), 7.84 (dd, J = 6.3, 3.6 Hz , 1H), 7.57-7.55 (m, 2H), 7.48 (d, J = 4.8 Hz, 1H), 7.20-7.13 (m, 2H), 6.89 (t, J = 6.6 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 5.26-5.20 (m, 1H), 4.23 (s, 2H), 3.98-3.88 (m, 1H), 2.17-1.99 (m, 2H), 1.52 (dd, J = 6.9, 4.8 Hz, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.10 (d, J = 8.1 Hz, 1H), 8.89 (d, J = 4.5 Hz, 1H), 7.67-7.57 (m, 2H), 7.52 -7.47 (m, 2H), 7.21-7.13 (m, 2H), 6.89 (t, J = 6.9 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 5.27-5.20 (m, 1H), 4.23 (s, 2H), 3.93-3.89 (m, 1H), 2.15-2.04 (m, 2H), 1.56-1.51 (m, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.09 (d, J = 8.1 Hz, 1H), 8.88 (d, J = 4.8 Hz, 1H), 7.72-7.66 (m, 1H), 7.57 (d, J = 4.5 Hz, 1H), 7.37 (t, J = 8.4 Hz, 2H), 7.22-7.13(m, 2H), 6.90 (td, J = 7.5, 0.9 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 5.25-5.23 (m, 1H), 4.26-4.22 (m, 2H), 3.93-3.89 (m, 1H), 2.16-2.03 (m, 2H), 1.55-1.51 (m, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 9.11 (d, J = 8.3 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 7.84 (q, J = 1.3 Hz, 3H), 7.61 (d, J = 4.8 Hz, 1H), 7.28-7.20 (m, 1H), 7.20-7.11 (m, 1H), 6.95-6.91 (m, 1H), 6.80 (d, J = 8.2 Hz, 1H) , 5.27 (q, J = 6.7 Hz, 1H), 4.28-4.25 (m, 2H), 3.96-3.92 (m, 1H), 2.20-1.99 (m, 2H), 1.51 (dd, J = 7.1, 5.0 Hz , 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.86 (d, J = 4.7 Hz, 1H), 7.74 (t, J = 1.6 Hz, 1H), 7.70 (t, J = 1.7 Hz, 1H), 7.67 (t, J = 1.8 Hz, 1H), 7.49 (d, J = 1.9 Hz, 2H), 7.43 (t, J = 1.8 Hz, 1H), 7.38 (d, J = 4.7 Hz, 1H), 7.32 ( d, J = 7.7 Hz, 1H), 7.27-7.19 (m, 1H), 7.02-6.84 (m, 2H), 6.25 (d, J = 7.5 Hz, 1H), 5.38 (q, J = 5.8 Hz, 1H ), 4.36 (ddd, J = 9.8, 6.2, 3.4 Hz, 1H), 4.23 (ddd, J = 11.6, 8.9, 2.9 Hz, 1H), 4.12 (p, J = 7.0 Hz, 1H), 2.48-2.32 ( m, 1H), 2.31-2.17 (m, 1H), 1.63 (dd, J = 7.1, 3.2 Hz, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.07 (d, J = 8.4 Hz, 1H), 8.98 (d, J = 2.1 Hz, 1H), 8.87 (d, J = 4.8 Hz, 1H ), 8.76 (dd, J = 4.8, 3.3 Hz, 1H), 8.23-8.19 (m, 1H), 7.67-7.62 (m, 2H), 7.24-7.14 (m, 2H), 6.91 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.30-5.23 (m, 1H), 4.26 (s, 2H), 3.98-3.91 (m, 1H), 2.18-2.04 (m, 2H) , 1.54-1.50 (m, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.09 (d, J = 8.4 Hz, 1H), 8.89 (d, J = 4.8 Hz, 1H), 8.82 (d, J = 4.5 Hz, 2H ), 7.80 (d, J = 4.5 Hz, 2H), 7.65 (d, J = 4.8 Hz, 1H), 7.25-7.14 (m, 2H), 6.91 (t, J = 7.2 Hz, 1H), 6.79 (d , J = 8.1 Hz, 1H), 5.30-5.23 (m, 1H), 4.26 (s, 2H), 3.97-3.86 (m, 1H), 2.22-2.03 (m, 2H), 1.53-1.50 (m, 6H) ) ppm.

1H-NMR (300 MHz, DMSO-d6): δ = 9.01 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 4.8 Hz, 1H), 7.25 (d, J = 4.5 Hz, 1H), 7.15 (t, J = 6.8 Hz, 1H), 5.25-5.15 (m, 1H), 4.25-4.35 (m, 2H), 3.75-3.85 (m, 3H), 2.51 (s, 2H), 2.05-2.20 ( m, 2H), 1.90-1.75 (m, 3H), 1.55 (t, J = 4.5 Hz, 6H), 1.40 (t, J = 4.5 Hz, 6H), 1.80 (dd, J = 4.5 Hz, J = 4.2 Hz, 1H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.70 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.18 (d, J = 4.5 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.26 (d, J = 6.9 Hz, 1H), 5.40- 5.38 (m, 1H), 4.37-4.34 (m, 1H), 4.29-4.25 (m, 1H), 4.11-4.07 (m, 1H), 3.10-3.07 (m, 1H), 2.40-2.36 (m, 1H) ), 2.29-2.26 (m, 1H), 1.80-1.75 (m, 1H), 1.60 (dd, J = 6.9, 3.0 Hz, 6H), 1.56-1.49 (m, 2H), 1.35 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 5.7 Hz, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.05 (d, J = 8.4 Hz, 1H), 8.65 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 4.8 Hz, 1H ), 7.26 (d, J = 7.5 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.81(d, J = 8.1 Hz, 1H), 5.31-5.24 (m, 1H), 4.33-4.23 (m, 2H), 3.90-3.81 (m, 1H), 3.27-3.22 (m, 1H), 2.18-2.02 (m, 4H), 1.84-1.75 (m , 6H), 1.50-1.46 (m, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.65 (d, J = 8.4 Hz, 1H), 7.35-7.25 (m, 2H), 7.21-7.16 (m, 1H), 6.90-6.85 ( m, 1H), 6.81 (d, J = 8.1 Hz, 1H), 5.35-5.29 (m, 1H), 4.33-4.23 (m, 2H), 3.90-3.81 (m, 1H), 3.90-2.75 (m, 1H), 2.35-2.05 (m, 2H), 2.01-1.80 (m, 5H), 1.80-1.3 (m, 11H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.69 (d, J = 4.7 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 19.3, 6.3 Hz, 2H ), 7.02-6.81 (m, 2H), 6.23 (d, J = 7.5 Hz, 1H), 5.35 (q, J = 6.1 Hz, 1H), 4.44-4.29 (m, 1H), 4.22 (t, J = 9.9 Hz, 1H), 4.06 (p, J = 7.3 Hz, 1H), 2.83 (s, 1H), 2.48-2.16 (m, 4H), 2.15-1.77 (m, 7H), 1.57 (dd, J = 7.4 , 3.2 Hz, 6H) ppm.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ = 9.04 (d, J = 8.3 Hz, 1H), 8.69 (d, J = 4.8 Hz, 1H), 7.36 (d, J = 4.8 Hz, 1H ), 7.30-7.13 (m, 2H), 7.00-6.88 (m, 1H), 6.87-6.76 (m, 1H), 6.50-6.42 (m, 1H), 5.34-5.20 (m, 1H), 4.34-4.20 (m, 2H), 3.98-3.78 (m, 1H), 2.64-2.53 (m, 2H), 2.23-2.00 (m, 4H), 1.63-1.53 (m, 2H), 1.53-1.43 (m, 6H) , 0.45-0.35 (m, 4H) ppm.

¹ H-NMR (300 MHz, DMSO- d ₆ ): δ = 9.05 (d, J = 8.2 Hz, 1H), 8.66 (d, J = 4.8 Hz, 1H), 7.46-7.12 (m, 3H), 7.03 -6.87 (m, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.27 (d, J = 6.4 Hz, 1H), 4.27 (s, 2H), 3.99-3.76 (m, 1H), 2.92- 2.71 (m, 1H), 2.30-2.04 (m, 2H), 2.02-1.68 (m, 6H), 1.48 (s, 6H), 0.99 (d, J = 12.6 Hz, 2H), 0.31 (d, J = 14.6 Hz, 4H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.26 (dt, J = 17.8, 7.8 Hz, 2H), 7.12 (s, 1H), 7.02-6.82 (m, 2H), 6.44 (s, 1H) , 6.24 (s, 1H), 5.36 (s, 1H), 4.34 (q, J = 6.3, 4.5 Hz, 1H), 4.22 (t, J = 9.6 Hz, 1H), 4.07 (q, J = 7.3 Hz, 1H), 3.39 (s, 2H), 2.92 (s, 2H), 2.72 (s, 2H), 2.30 (d, J = 33.9 Hz, 2H), 1.57 (s, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.30 (d, J = 7.6 Hz, 1H), 7.25-7.15 (m, 2H), 7.03-6.76 (m, 2H), 6.21 (d, J = 7.5 Hz, 1H), 5.36 (d, J = 6.6 Hz, 1H), 4.44-4.29 (m, 1H), 4.22 (dd, J = 11.2, 8.2 Hz, 1H), 4.04 (p, J = 7.0 Hz, 1H), 3.33-3.11 (m, 4H), 3.00 (t, J = 12.2 Hz, 1H), 2.55 (s, 2H), 2.45-2.15 (m, 4H), 1.56 (d, J = 7.1 Hz, 6H ) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.81 (dd, J = 5.0, 1.6 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 7.72-7.49 (m, 2H), 7.34 (dd, J = 4.7, 1.7 Hz, 1H), 7.26 (d, J = 1.7 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.00-6.79 (m, 2H), 5.30 (q, J = 6.0 Hz, 1H), 4.41-4.28 (m, 1H), 4.20 (dd, J = 11.4, 8.0 Hz, 1H), 2.42-2.17 (m, 2H), 2.01 (dd, J = 24.1, 4.8 Hz , 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.82 (d, J = 4.8 Hz, 1H), 8.59 (d, J = 5.1 Hz, 1H), 7.62 (d, J = 1.3 Hz, 1H), 7.54 (dd, J = 5.1, 1.6 Hz, 1H), 7.37 (d, J = 4.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 7.4 Hz, 1H), 5.31 (d, J = 7.1 Hz, 1H), 4.40- 4.29 (m, 1H), 4.26-4.13 (m, 1H), 2.34 (dd, J = 9.8, 4.5 Hz, 1H), 2.27-2.13 (m, 1H), 1.88 (d, J = 3.9 Hz, 5H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 10.59 (d, J = 4.0 Hz, 1H), 8.56 (d, J = 5.4 Hz, 1H), 7.26-7.22 (m, 2H), 6.95-6.88 (m, 2H), 6.76 (d, J = 5.4 Hz, 1H), 5.31-5.28 (m, 1H), 4.39-4.11 (m, 2H), 3.80-3.67 (m, 4H), 3.45-3.37 (m , 8H), 2.40-2.20 (m, 6H) ppm.

1H-NMR (300 MHz, DMSO-d6): δ = 10.56 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 4.4 Hz, 1H), 7.25-7.19 (m, 1H), 7.00-6.81 (m, 3H), 5.15 (m, 1H), 4.35-4.25 (m, 1H), 4.15-4.10 (m, 1H), 3.92-3.85 (m, 2H) ), 3.45-3.10 (m, 6H), 2.55-2.50 (b, 2H), 2.25-2.15 (m, 2H), 1.90-1.75 (m, 3H), 1.90 (d, J = 4.5 Hz, 6H), 1.85 (dd, J = 4.4 Hz, J = 4.1 Hz, 1H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.99 (d, J = 8.1 Hz, 1H), 8.86 (d, J = 5.4 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H ), 7.18 (t, J = 6.6 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 5.4 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.29-5.23 (m, 1H), 4.32-4.22 (m, 2H), 3.89-3.80 (m, 1H), 3.38 (d, J = 4.8 Hz, 4H), 2.17-2.06 (m, 2H), 1.68 ( s, 6H), 1.41-1.49 (m, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.38 (d, J = 5.4 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.34 (d, J = 5.1 Hz, 1H), 6.23 (d, J = 6.3 Hz, 1H), 5.36- 5.32 (m, 1H), 4.85 (s, 1H), 4.73 (s, 1H), 4.38-4.31 (m, 1H), 4.24-4.17 (m, 1H), 4.07-3.92 (m, 3H), 3.84 ( d, J = 9.3 Hz, 1H), 3.66 (d, J = 8.7 Hz, 1H), 2.39-2.31 (m, 1H), 2.25-2.20 (m, 1H), 2.07 (s, 2H), 1.54 (dd , J = 6.6, 4.8 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.38 (d, J = 5.7 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 6.9 Hz, 1H), 6.99 (td, J = 7.2, 1.2 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 5.7 Hz, 1H), 6.24 (d, J = 6.3 Hz, 1H), 5.38-5.36 (m, 1H), 4.75 (d, J = 6.3 Hz, 2H), 4.69 (d, J = 6.3 Hz, 2H), 4.37-4.34 (m, 1H), 4.28-4.24 (m, 1H) , 4.08-4.01 (m, 3H), 3.79-3.75 (m, 2H), 2.42-2.36 (m, 3H), 2.29-2.26 (m, 1H), 1.56 (dd, J = 6.9, 3.9 Hz, 6H) ppm.

¹ H-NMR: (300 MHz, DMSO-d ₆ ): δ = 9.62 (d, J = 8.1 Hz, 1H), 8.97 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 4.8 Hz, 1H), 7.67-7.50 (m, 3H), 7.25 (d, J = 7.5 Hz, 1H), 7.22-7.13 (td, J = 7.5, 1.2 Hz, 1H), 6.93 (td, J = 7.5, 1.2 Hz , 1H), 6.81 (dd, J = 8.1, 1.2 Hz, 1H), 5.23 (q, J = 6.0 Hz, 1H), 4.24 (m, 2H), 2.19 (m, 1H), 2.07-2.00 (m, 1H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.52 (d, J = 8.1 Hz, 1H), 8.96 (d, J = 4.8 Hz, 1H), 7.75 (d, J = 4.8 Hz, 1H ), 7.62 (m, 3H), 7.26-7.15 (m, 2H), 6.92 (td, J = 7.5 Hz, 0.9 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 5.22 (d, J = 7.8 Hz, 1H), 4.27-4.18 (m, 2H), 2.19-2.16 (m, 1H), 2.08-1.98 (m, 1H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.70 (d, J = 4.5 Hz, 1H), 7.32 (d, J = 6.6 Hz, 1H), 7.24-7.21 (m, 1H), 7.16 (d , J = 4.8 Hz, 1H), 6.99-6.94 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.22 (d, J = 6.6 Hz, 1H), 5.37-5.35 (m, 1H) , 4.35-4.32 (m, 1H), 4.26-4.16 (m, 1H), 4.12-4.05 (m, 3H), 3.63-3.56 (m, 2H), 3.01-2.96 (m, 1H), 2.38-2.35 ( m, 1H), 2.26-2.23 (m, 1H), 2.03-1.87 (m, 4H), 1.59-1.54 (m, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.71 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.26-7.21 (m, 1H), 7.16 (d , J = 4.8 Hz, 1H), 6.98-6.93 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.46 (s, 1H), 6.22 (d, J = 7.2 Hz, 1H), 5.38 -5.35 (m, 1H), 4.40-4.31 (m, 3H), 4.26-4.18 (m, 1H), 4.10-4.06 (m, 1H), 3.98 (t, J = 5.4 Hz, 2H), 2.60-2.58 (m, 2H), 2.38-2.31 (m, 1H), 2.28-2.22 (m, 1H), 1.59-1.52 (m, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.70 (d, J = 4.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 4.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.36 (s, 1H), 6.21 (d, J = 6.6 Hz, 1H), 5.41-5.34 (m, 1H), 4.36-4.31 (m, 1H), 4.26-4.22 (m, 1H), 4.19-4.06 (m, 1H), 2.58-2.33 (m, 6H), 2.27-2.19 (m, 2H), 1.86-1.72 (m, 1H), 1.57 (dd, J = 6.9, 3.0 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.69 (d, J = 4.8 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 5.7 Hz, 1H), 6.99 (t, J = 8.4 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.5 Hz, 1H), 5.37- 5.34 (m, 1H), 4.35-4.32 (m, 1H), 4.26-4.22 (m, 1H), 4.08-4.04 (m, 1H), 2.89-2.87 (m, 1H), 2.40-2.27 (m, 2H) ), 2.26-2.13 (m, 1H), 2.12-2.06 (m, 2H), 2.01-1.79 (m, 6H), 1.57 (dd, J = 7.2, 3.3 Hz, 6H) ppm.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.70 (d, J = 4.8 Hz, 1H), 7.32-7.22 (m, 2H), 7.14 (d, J = 4.8 Hz, 1H), 6.96 (t , J = 7.4 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.21 (s, 2H), 5.35 (q, J = 5.9 Hz, 1H), 4.40- 4.33 (m, 1H), 4.58 -4.20 (m, 1H), 4.14-4.05 (m, 1H), 2.90-2.69 (m, 4H), 2.43-2.14 (m, 4H), 1.58 (dd, J = 6.1, 3.0 Hz, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d6): δ = 9.12 (d, J = 8.1 Hz, 1H), 8.86 (d, J = 4.5 Hz, 1H), 7.62-7.46 (m, 4H), 7.06- 7.00 (m, 2H), 6.85-6.80 (m, 1H), 5.27-5.24 (m, 1H), 4.26-4.23 (m, 2H), 3.97-3.92 (m, 1H), 2.14-2.04 (m, 2H) ), 1.51 (dd, J = 7.0, 4.7 Hz, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.12 (d, J = 8.1 Hz, 1H), 8.89 (d, J = 4.8 Hz, 1H), 7.83-7.78 (m, 1H), 7.59 (d, J = 4.8 Hz, 1H), 7.54-7.50 (m, 1H), 7.06-6.99 (m, 2H), 6.84-6.80 (m, 1H), 5.25 (q, J = 6.6 Hz, 1H), 4.25-4.22 (m, 2H), 3.95-3.90 (m, 1H), 2.14-2.02 (m, 2H), 1.52 (dd, J = 6.9, 4.8 Hz, 6H) ppm.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.10 (d, J = 8.4 Hz, 1H), 8.88 (d, J = 4.8 Hz, 1H), 7.82-7.78 (m, 1H), 7.57 (d, J = 4.5 Hz, 1H), 7.52-7.48 (m, 1H), 7.22-7.13 (m, 2H), 6.90 (td, J = 7.5, 1.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.25 (q, J = 6.6 Hz, 1H), 4.24-4.22 (m, 2H), 3.94-3.89 (m, 1H), 2.14-2.06 (m, 2H), 1.52 (dd, J = 7.0, 4.8 Hz, 6H) ppm.

Biological examples The present invention is further illustrated by the following biological examples, which should not be construed as limiting the scope or spirit of the present invention to the specific procedures described herein. It should be understood that the examples provided are used to illustrate certain embodiments and are not intended to limit the scope of the present invention. It should be further understood that a variety of other embodiments, variations and equivalent forms can be used, and those familiar with the art can think of the other implementations without departing from the spirit of the present invention and/or the scope of the appended patent application. Examples, variants and their equivalent forms.

Example 1 : Screening method for testing the activity of compounds against Microfilaria canis. Four hundred to six hundred heartworm microfilariae are added to the wells of the microtiter plate containing the RPMI medium and the test compound formulated in 100% DMSO. Keep the culture plate at 37°C and 5% CO _{2 for three days.} The efficacy of the compound was determined based on the comparison of the activity of the microfilariae and the average activity of the control wells containing only DMSO. Dose response analysis to determine values ₅₀ EC. Compounds 310, 228, 217, 301, 205, and 259-4 exhibited EC ₅₀ values between 100 nM and 10 μM. 259-5,260,258,220,222,203,213,199,229,224,221,247 compound and 214 exhibit EC ₅₀ values between 10 nM and 100 nM. Compounds 236, 243, 238, 256, 253, 252, 337, 212-0, 207, 120, 102, 259, 264, 211, 210, 263, 263-8, 204, 311, 309, 212, 209, 206 223 and ₅₀ exhibit values of less than the EC 10 nM.

Example 2 : Screening method for testing compound activity against Haematodia contortus. Twenty L1 Haemonchus contortus larvae were added to the wells of the microtiter plate containing nutrient medium and DMSO containing the test compound. Analysis was performed on the 4th day to determine the degree of development of the larvae from L1 to L3. Larvae exposed to DMSO alone served as controls. Dose response analysis to determine values ₅₀ EC. Found compounds 124, 090, 205, 236, 238, 256, 246, 337, 128, 207, 119, 260, 102, 338, 268-4, 268, 220, 222, 255, 255-0, 243, 213, 201, 229, 223, 115, 126, 127, 129, 102-1, 101, 130, 121, 092, 239-INT-1, 239, 240, 241, 249, 245, 242 and 123 are active and have _{EC 50} value between 100 nM and 10 μM. Compound 263-8, 263, 210, 204, 211, 336, 259-5, 264, 309, 264-0, 259, 285, 212, 120, 258, 212-0, 310, 252, 209, 253, 206 , 203 and 199 exhibit EC ₅₀ values less than 100 nM.

Example 3 : In vivo efficacy against heartworm canis in immunodeficient NSG mice The following in vivo study used to evaluate the effectiveness of the compounds of the present invention in preventing heartworm infection in mammals is based on WO 2018/148392 A1 ( It is incorporated by reference into the procedure described in). For the following research, the filariasis research reagent resource center (Filariasis Research Reagent Resource Center) of the University of Georgia Vet School (referred to as "FR3" in this article) and from the internal insect breeding room insect. Generally speaking, worms are recovered from mosquitoes and transported overnight in culture medium and antibiotics. The worms were washed and counted for use in mice. On day 0, 50 L3 heartworms (2005 Missouri isolate or JYD-34) were injected into immunodeficient NSG mice susceptible to heartworm infection by subcutaneous or intraperitoneal injection. On days 1, 15 and 30 after infection, NSG mice were orally administered with the compound of the present invention at the dose indicated in the study.

For the recovery of parasites, mice were bled for serum collection at 6 weeks after infection, skin was peeled and fascia was obtained, organs (viscers) were removed, and muscle fascia was obtained. Soak all pieces in RPMI medium supplemented with 10% FBS and Pen/strep antibiotics at room temperature overnight. The next morning, approximately 18 hours later, the worms were counted and fixed in 95% ethanol/5% glycerol. The worms were put into glycerin glue and then measured using cellSens software.

the study 1 Set up four groups, each with six immunodeficient NSG mice. An untreated group served as a control, and the other three groups were given compounds 211, 204, and 212 at doses of 25 mg, 50 mg, and 25 mg per kilogram of body weight, respectively. These compounds are formulated in Labrasol/Labrifil at a concentration of 2.5 mg/mL^® M 1944 CS (70:30) carrier, and the dose indicated in the table below was orally administered to mice. The efficacy of the compound was evaluated against mice that were not administered to the control group. Table 6 below shows the percentage reduction of live worms recovered from the treated group compared to the control group. Table 6 Compound number Dose (mg/kg) Worm reduction % P value 211 25 61 0.002 204 50 65 0.002 212 twenty three 13 0.501

the study 2 Using a protocol similar to that of Study 1, the efficacy of two different doses of compound 119 and 120 was studied. Assign 6 NSG mice to the control group. Four groups were studied, each with 5 NSG mice, and each group was allocated to administer compounds 119 and 120 at doses of 25 mg and 50 mg per kilogram of body weight. These compounds were formulated in Labrasol/Labrifil at a concentration of 2.5 mg/mL as in Study 1.^® M 1944 CS (70:30) carrier, and the doses indicated in Table 7 below were orally administered to mice. Table 7 Compound number Dose (mg/kg) Worm reduction % P value 119 25 67 0.000 119 50 37 0.005 120 25 47 0.003 120 50 33 0.009

the study 3 Using a protocol similar to Study 1, the efficacy of compounds 210, 257, 207, and 102 was studied. Assign 7 NSG mice to the control group. Four other test groups were assigned to administer compounds 210, 257, 207, and 102. The group used for compound 210 contained 7 NSG mice, and the groups used for compound 257, 207, and 102 each contained 6 NSG mice. The compound was formulated in Labrasol/Labrifil at a concentration of 2.5 mg/mL as in Study 1.^® M 1944 CS (70:30) carrier, and was orally administered to mice at a dose of 25 mg per kilogram of body weight. The results of the study are shown in Table 8 below. Table 8 Compound number Worm reduction % P value 210 55 0.008 257 45 0.028 207 55 0.010 102 50 0.018

Therefore, it is believed that the compound of the present invention has activity against Heartworm canis in the NSG mouse model.

Example 4: In vivo efficacy against Haemonchus contortus and Trichostrongylus serpentinus in Mongolian Jird (Meriones unguiculatus). Several in vivo studies were carried out to test the efficacy of the compounds of the present invention on Haematodia contortus and Trichostrongylus serpentinus in Mongolian gerbils. The groups of 5 animals were assigned to each treatment group, an untreated control group and a positive control group. ^{Labrasol/Labrifil ®} M 1944 CS (70:30) vehicle was administered to gerbils in the untreated control group. Animals in the positive control group were treated with levamisole (10 mg/kg in water vehicle) and/or ivermectin (0.1 mg/kg in DMSO/corn oil (50%/50% v/v)) . On day 0, the immunosuppressed Mongolian gerbils were artificially infected with about 1,000 infectious third-instar larvae of Haematocodon contortus. At least 4 hours later, the gerbils were also infected with about 1,000 third-instar larvae of Trichostrongylus serpentinus. Six days after infection, the gerbils were treated with the test compound ^{dissolved in the Labrasol/Labrifil ®} M 1944 CS (70:30) mixture by oral gavage at the dose indicated in Tables 9 to 12 below. On the 9th day (3 days after treatment), the gerbils were euthanized and autopsied to recover parasites from the stomach and small intestine. Efficacy was calculated in the form of an average reduction in% of the number of worms in each test group compared to the average number of worms in the control group. The efficacy of the tested compounds is presented in Tables 9 to 12 below.

the study 1 : Table 9 Compound number Dose (mg/kg) Haemaphysalis contortus reduced by % Trichostrongylus serpentine reduced % 263 25 100.0 100.0 285 25 100.0 100.0 Levamisole 10 98.4 89.1 Ivermectin 0.1 66.1 92.9

the study 2 : Table 10 Compound number Dose (mg/kg) Haemaphysalis contortus reduced by % Trichostrongylus serpentine reduced % 263-8 25 99.8 100.0 Levamisole 10 100.0 96.4

the study 3 : Table 11 Compound number Dose (mg/kg) Haemaphysalis contortus reduced by % Trichostrongylus serpentine reduced % 211 25 100.0 100.0 204 25 100.0 100.0 210 25 100.0 100.0 Levamisole 10 100.0 100.0

Study 4: Table 12 Compound number Dose (mg/kg) Haemaphysalis contortus reduced by % Trichostrongylus serpentine reduced % 204 5 50.1 22.2 259 25 100.0 99.5 260 25 23.5 45.8 263-8 5 99.8 99.9 Levamisole 10 99.8 72.2

Therefore, it is believed that the compound of the present invention is highly effective against Haematocodon contortus and Trichostrongylus serpentinus in Mongolian gerbil models. * * *

From this detailed description of the preferred embodiments of the present invention, it should be understood that the present invention defined by the above paragraphs is not limited to the specific details described in the above description, because many obvious changes can be made without departing from the spirit or scope of the present invention. To proceed.

Claims (29)

A compound of formula I:

, Or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, where: L is L1 or L2:

; R ¹ is hydrogen, cyano, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted hetero Cyclic, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl,- SO _p (optionally substituted alkyl or haloalkyl of), - SF _5, or -NR ^a R ^b, wherein R ^a and R ^b are independently H or optionally substituted alkyl of; or R ^a and R ^b may form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group with the nitrogen to which it is attached, and the heterocyclic group may include one to three selected from the group consisting of N, O and S additional heteroatoms and optionally substituted; R ² is hydrogen, optionally substituted alkyl of, the optionally substituted cycloalkyl or optionally substituted aryl group of; R ^{2 'is} optionally substituted alkyl of , Optionally substituted cycloalkyl or optionally substituted aryl; R ³ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkylcarbonyl, optionally substituted Substituted alkoxycarbonyl, aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -S(O) _p (optionally substituted alkyl), -SF ₅ , optionally substituted heterocyclic group, optionally substituted 6- to 10-membered aryl group, optionally substituted 5- to 10-membered heteroaryl group, spirocyclic heterocyclic group-carbocyclic group, spiro heterocyclyl - heterocyclyl, spiro carbocyclic group - carbocyclyl, carbocyclyl spiro - heterocyclic group or -NR ^a R ^b, wherein R ^a and R ^b are independently H or an optionally Substituted alkyl; or R ^a and R ^b together with the nitrogen to which they are attached can form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group, which may include one to three options Free additional heteroatoms of the group consisting of N, O and S and may be substituted as appropriate; R ⁴ is independently hydrogen, cyano, halo, hydroxyl, optionally substituted alkyl, optionally substituted Substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally In the case of substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted heterocyclic group, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted Substituted aminocarbonyl, optionally substituted alkylaminocarbonyl, optionally substituted dialkylaminocarbonyl, -SO _p (optionally substituted alkyl or haloalkyl), -SF ₅ or -NR ^a R ^b, wherein R ^a and R ^b are independently H or optionally substituted alkyl of; or together with R ^a and R ^b may be the nitrogen to which they are attached 3 R ⁵ and R ^{5 'at} each occurrence is independently hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted alkyl of, the optionally substituted alkoxy group, the optionally substituted cycloalkyl, Optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted heteroaryl, -SF ₅ , -SO _p (optionally substituted alkyl or haloalkyl) or- NR ^c R ^d , where R ^c and R ^{d are} independently H or optionally substituted alkyl; or R ^c and R ^d can form 3, 4, 5, 6 members together with the nitrogen to which they are attached, A 7-membered or 8-membered heterocyclic group, the heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O and S and may be substituted as appropriate; R ¹⁰ is hydrogen, halogen, alkyl, haloalkane Group, cycloalkyl, alkenyl or alkynyl; X is O or S; Q is O, S or NR ^2' ; Y ¹ , Y ² and Y ³ are each independently -N- or -CR ⁴ -; Y ^{1 'and} Y ^6' are each independently N, C, or ^{-CR 5 -; Y 2 ',} Y 3', Y 4 ', Y 5' are each independently ^{N, NR 2, S, O} , -CR 5 -Or CR ⁵ R ^5' ; W is CR ⁶ R ⁷ , O, S or NR ⁸ , Z is CR ⁶ R ⁷ , O, S or NR ⁸ , where R ⁶ and R ⁷ are independently each time Hydrogen, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or C ₃ -C ₈ cycloalkoxy ; R ⁸ is hydrogen or C ₁ -C ₄ alkyl; and wherein ^{Y 1 ', Y 2',} Y 3 ', Y 4', up to three of the Y ^{5 'and} Y ^6' is a heteroatom; a is 0 or 1; q is 0 or 1; p is independently 0, 1 or 2 each time it appears; and the dashed key (

) Represents a single bond or a double bond. For example, the compound of formula (I) in claim 1 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein: R ¹ Is hydrogen, cyano, halo, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, hydroxy -C ₁ -C ₆ alkyl, hydroxy -C ₁ -C ₆ haloalkyl, C _1- C ₆ alkoxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkoxy-C ₁ -C ₆ alkyl, amino-C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ haloalkynyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ alkylamine Carbonyl, C ₁ -C ₆ haloalkylaminocarbonyl, di-C ₁ -C ₆ alkylaminocarbonyl, di-C ₁ -C ₆ haloalkylaminocarbonyl, optionally substituted aryl, Optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkyloxy, optionally substituted Substituted 3-membered to 7-membered heterocyclic group, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxy Carbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ haloalkylaminocarbonyl, di-C ₁ -C ₆ alkylaminocarbonyl, di-C ₁ -C ₆ halo alkylaminocarbonylamino group, -SF _5, -SO _p (optionally substituted alkyl group of C ₁ -C ₆ or a halo C ₁ -C ₆ alkyl), or -NR ^a R ^b, wherein R ^a and R ^{b are} independently is H or optionally substituted alkyl of C ₁ -C _6; or R ^a and R ^b may be taken together with the nitrogen to which they are attached 3, 4, 5, 6, 7 or 8-membered heterocyclic ring The heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O and S and may be substituted as appropriate; R ² is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halo Alkyl, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted phenyl; R ^2'is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted phenyl; R ³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy-C _1- C ₆ alkyl, C ₁ -C ₆ haloalkoxy-C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkylcarbonyl, C _1- C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ haloalkane Aminocarbonyl, di-C ₁ -C ₆ alkylaminocarbonyl, di-C ₁ -C ₆ haloalkylaminocarbonyl, -SF ₅ , -S(O) _p (C ₁ -C ₆ alkyl Or C ₁ -C ₆ haloalkyl), optionally substituted 3- to 7-membered heterocyclic group containing one to three heteroatoms selected from the group consisting of N, O and S, optionally substituted phenyl , Optionally substituted 5-membered to 10-membered heteroaryl, 5-membered to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5-membered to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5-membered to 11-membered spiro carbocyclic group - carbocyclyl, 5-11 spiro carbocyclic group - heterocyclyl or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; or R ^a and R ^b may form a 3, 4, 5, 6, 7 or 8-membered heterocyclic group together with the nitrogen to which they are attached, the heterocyclic group include One to three additional heteroatoms selected from the group consisting of N, O and S and can be substituted as appropriate; ^{each occurrence of R 4} is independently hydrogen, cyano, halo, hydroxy, C ₁ -C ₆ alkyl , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ haloalkynyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkoxy-C ₁ -C ₆ alkyl, as appropriate Substituted phenyl, optionally substituted phenoxy, optionally substituted 5- or 6-membered heteroaryl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkyloxy group, optionally substituted 3- to 7-membered heterocyclic group containing one to three heteroatoms selected from the group consisting of N, O and S, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ haloalkylaminocarbonyl, di-C ₁ -C ₆ alkylaminocarbonyl, di-C ₁ -C ₆ haloalkylaminocarbonyl, -SO _p (optionally substituted C ₁ -C ₆ alkane group or halo C ₁ -C ₆ alkyl), SF _5, or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or R ^a and R ^b can form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group together with the nitrogen to which they are attached, and the heterocyclic group may include one to three selected from N, O and S The additional heteroatoms of the group that constitute the group can be substituted as appropriate; R ⁵ and R ^5'are in each output Currently independently hydrogen, halogen, cyano, nitro, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy Group, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkoxy-C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl , Optionally substituted C ₃ -C ₈ cycloalkyloxy, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, -SF ₅ , -SO _p (as the case may be Substituted C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl) or -NR ^c R ^d , wherein R ^c and ^{Rd are} independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ Haloalkyl; or R ^c and R ^d together with the nitrogen to which they are attached can form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group, which may include one to three selected from The additional heteroatoms of the group consisting of N, O and S can be optionally substituted; and R ¹⁰ is hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₈ cycloalkane Group, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl. If the compound of formula (I) of claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein R ¹ is hydrogen, cyano, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, optionally substituted C ₂ -C ₄ alkenyl, optionally substituted Substituted C ₂ -C ₄ alkynyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted saturated or unsaturated 5-membered, 6-membered or 7-membered heterocyclic ring, optionally substituted aromatic Group, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted C ₁ -C ₄ alkylcarbonyl, optionally substituted C ₁ -C ₄ alkoxycarbonyl, Optionally substituted aminocarbonyl, optionally substituted C ₁ -C ₄ alkylaminocarbonyl, optionally substituted C ₁ -C ₄ dialkylaminocarbonyl, optionally substituted alkyl- SO _p -, haloalkyl -SO _p -, amino, -NH- of optionally substituted C ₁ -C ₄ alkyl or -NR ^a R ^b, wherein R ^a and R ^b are independently optionally substituted的alkyl; or R ^a and R ^b can form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group together with the nitrogen to which they are attached, and the heterocyclic group may be substituted as appropriate; R ² Is hydrogen or C ₁ -C ₄ alkyl; R ³ is C ₁ -C ₄ alkyl, 6 to 10-membered aryl, 5- to 10-membered heteroaryl, C ₃ -C ₈ cycloalkyl, 5-membered To 11-membered spirocyclic heterocyclyl-carbocyclyl, 5-membered to 11-membered spirocyclic heterocyclyl-heterocyclic group, 5-membered to 11-membered spirocyclic carbocyclyl-carbocyclyl or 5-membered to 11-membered spiro ring Carbocyclyl-heterocyclic group, each of which may be substituted with 1, 2 or 3 substituents as appropriate; R ^{4 is} independently hydrogen, halogen, cyano, nitro, -OH, optionally substituted C _1- C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, optionally substituted C ₃ -C ₈ cycloalkyl, amino, NH- optionally substituted C ₁ -C ₄ alkyl group, -SF _5, or -NR ^a R ^b, wherein R ^a and R ^b are independently optionally substituted alkyl group of C ₁ -C _4; or R ^a and R ^b together with the nitrogen can form a visible they are attached A substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocyclic group, -SO _p (optionally substituted C ₁ -C ₄ alkyl or haloalkyl); and R ⁵ Independently halogen, cyano, nitro, -OH, optionally substituted C ₁ -C ₄ alkyl, optionally substituted C ₁ -C ₄ alkoxy, optionally substituted C ₃ -C ₈ Cycloalkyl, amino, NH-optionally substituted C ₁ -C ₄ alkyl, -SF ₅ or -NR ^c R ^d , wherein R ^c and ^{Rd are} independently optionally substituted C _1- C ₄ alkyl; or R ^c and R ^d can be The connected nitrogens together form optionally substituted 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group, -SO _p (optionally substituted C ₁ -C ₄ alkyl or haloalkane base). For example, the compound of formula (I) of claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein X For S. For example, the compound of formula (I) of claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein X Is O. Such as the compound of formula (I) of claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein a Is 1 and q is 1. Such as the compound of formula (I) of claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein a Is 0 and q is 0. Such as the compound of formula (I) of claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein a Is 1 and q is 0. The compound of formula (I) according to claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein: L is L1; R ¹ is halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ haloalkyl, alkoxy Group-C ₁ -C ₄ alkyl, alkoxy-C ₁ -C ₄ haloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ haloalkenyl, C ₂ -C ₄ alkynyl, C ₂ -C ₄ haloalkynyl, C ₁ -C ₄ alkylcarbonyl, C ₁ -C ₄ haloalkylcarbonyl, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₄ haloalkoxycarbonyl, aminocarbonyl , C ₁ -C ₄ alkylaminocarbonyl, C ₁ -C ₄ haloalkylaminocarbonyl, di-C ₁ -C ₄ alkylaminocarbonyl, di-C ₁ -C ₆ haloalkylaminocarbonyl , Optionally substituted 5-membered or 6-membered heteroaryl group containing 1 to 3 N, S or O heteroatoms or optionally substituted 5-membered or 6-membered heterocyclic group or -NR ^a R ^b , wherein R ^a and R ^b are independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; or R ^a and R ^b may be taken together with the nitrogen to which they are attached 3, 4, 5 or 6 A membered heterocyclic group, which may include one to three additional heteroatoms selected from the group consisting of N, O and S and optionally substituted; R ² is hydrogen or C ₁ -C ₄ alkyl; R ³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, optionally substituted C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ haloalkylaminocarbonyl, di- C ₁ -C ₆ alkylaminocarbonyl, di-C ₁ -C ₆ haloalkylaminocarbonyl, -SO _p (optionally substituted C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl ), -SF ₅ , optionally substituted 3- to 7-membered heterocyclic group containing one to three heteroatoms selected from the group consisting of N, O and S, optionally substituted phenyl, optionally substituted 5-membered or 6-membered heteroaryl, 5-membered to 11-membered spirocyclic heterocyclyl-carbocyclyl, 5-membered to 11-membered spirocyclic heterocyclyl-heterocyclyl, 5-membered to 11-membered spirocyclic carbocyclyl - carbocyclyl, wherein each of the spiro ring-containing group of 5 or 6 ring atoms; or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₆ alkyl Or C ₁ -C ₆ haloalkyl; or R ^a and R ^b can form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic group together with the nitrogen to which they are attached, the heterocyclic group Can include one to three additional heteroatoms selected from the group consisting of N, O, and S and may be selected Substituted; ^{each occurrence of R 4} is independently hydrogen, halo, -SF ₅ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₂ -C ₄ alkenyl, C ₂ -C ₄ haloalkenyl, C ₂ -C ₄ alkynyl, C ₂ -C ₄ haloalkynyl, optionally substituted C _3- C ₆ cycloalkyl, C ₁ -C ₄ alkylcarbonyl, C ₁ -C ₄ haloalkylcarbonyl, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₄ haloalkoxycarbonyl, aminocarbonyl, C ₁ -C ₄ alkylaminocarbonyl, C ₁ -C ₄ haloalkylaminocarbonyl, di-C ₁ -C ₄ alkylaminocarbonyl, di-C ₁ -C ₄ haloalkylaminocarbonyl, -SO _p (optionally substituted alkyl group of C ₁ -C ₄ halo or C ₁ -C ₄ alkyl), or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₄ alkoxy Group or C ₁ -C ₄ haloalkyl; R ⁵ is independently hydrogen, halogen, -SF ₅ , C ₁ -C ₆ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C each time it occurs ₄ alkoxy, C ₁ -C ₄ haloalkoxy, -SO _p (optionally substituted alkyl group of C ₁ -C ₄ halo or C ₁ -C ₄ alkyl), or -NR ^c R ^d, wherein R ^c and R ^{d are} independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; R ¹⁰ is hydrogen, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; Q is O or S; Z is O; and W is CR ⁶ R ⁷ . If the compound of formula (I) of claim 9 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein a is 1 And q is 1. For example, the compound of formula (I) of claim 9 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein a is 0 Or 1 and q is 0. If the compound of formula (I) in claim 9 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, it is determined from the following The structure of formula (IC) means:

Wherein R ^{9 is} independently halo, cyano, nitro, C ₃ -C ₈ cycloalkyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ halocycloalkyl , C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ Haloalkyl; R ¹ is halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-C ₁ -C ₄ alkyl, alkoxy-C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ haloalkenyl, C ₂ -C ₄ alkynyl, C ₂ -C ₄ haloalkynyl, C ₁ -C ₄ alkylcarbonyl, C ₁ -C ₄ haloalkyl Carbonyl, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₄ haloalkoxycarbonyl, aminocarbonyl, C ₁ -C ₄ alkylaminocarbonyl, C ₁ -C ₄ haloalkylaminocarbonyl, Di-C ₁ -C ₄ alkylaminocarbonyl, di-C ₁ -C ₆ haloalkylaminocarbonyl, optionally substituted 5 or 6 members containing 1 to 3 N, S or O heteroatoms heterocyclyl or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; or R ^a and R ^b may be the nitrogen to which they are attached Together to form a 3-membered, 4-membered, 5-membered or 6-membered heterocyclic group, the heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O and S and may be substituted as appropriate; R ^{4 is} in each The second occurrence is independently hydrogen, halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, -SO _p (the optionally substituted C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl), - SF _5, or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₄ Alkyl or C ₁ -C ₄ haloalkyl; R ⁵ is halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ halo Alkoxy, -SO _p (optionally substituted C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl), -SF ₅ or -NR ^c R ^d , where R ^c and ^{Rd are} independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; W is CR ⁶ R ⁷ ; R ² is hydrogen or C ₁ -C ₃ alkyl; R ¹⁰ is hydrogen; o is 0, 1 or 2; and m is 0, 1, 2 or 3. For example, the compound of formula (I) in claim 9 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, which has the following structure Means:

Wherein: R ^{9 is} independently halo, cyano, nitro, C ₃ -C ₈ cycloalkyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ halocycloalkane group, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; R ¹ is halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-C ₁ -C ₄ alkyl, alkoxy-C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ haloalkenyl, C ₂ -C ₄ alkynyl, C ₂ -C ₄ haloalkynyl, C ₁ -C ₄ alkylcarbonyl, C ₁ -C ₄ haloalkane Carbonyl, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₄ haloalkoxycarbonyl, aminocarbonyl, C ₁ -C ₄ alkylaminocarbonyl, C ₁ -C ₄ haloalkylaminocarbonyl , Di-C ₁ -C ₄ alkylaminocarbonyl, di-C ₁ -C ₆ haloalkylaminocarbonyl, optionally substituted 5 members or 6 containing 1 to 3 N, S or O heteroatoms membered heterocyclyl or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or R ^a and R ^b which they are attached may The nitrogens together form a 3-membered, 4-membered, 5-membered or 6-membered heterocyclic group, which may include one to three additional heteroatoms selected from the group consisting of N, O, and S, and may optionally be substituted; R ⁴ is Each occurrence is independently hydrogen, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, -SO _p (optionally substituted alkyl group of C ₁ -C ₄ or C ₁ -C ₄ haloalkyl), - SF _5, or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; R ⁵ and R ^{5 'at} each occurrence is independently hydrogen, halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, -SO _p (optionally substituted C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl), -SF _{5 or-} NR ^c R ^d , wherein R ^c and R ^{d are} independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; R ² is hydrogen or C ₁ -C ₃ alkyl; R ¹⁰ is hydrogen ; Z is CR ⁶ R ⁷ or O; Y ^{1 'and} Y ^6' are each independently C, N or ^{CR 5; Y 3 ', Y} 4', Y 5 ' is independently CR ^5, CR ⁵ R ^5' , N, NR ² , O or S; dashed key (

) Represents a single bond or a double bond; a is 0 or 1; and m is 0, 1, 2 or 3. For example, the compound of formula (I) of claim 13 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein Y ^1' and Y ^{6 'are} each C; Y ^3' and Y ^{4 'are} independently CR ^5; and Y ^5' is S. For example, the compound of formula (I) of claim 13 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein Y ^3' and Y ^{6 'is} N; Y ^1' are C; and Y ^{4 'and} Y ^5' is independently CR ^5. For example, the compound of formula (I) of claim 13 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein Y ^1' and Y ^{5 'is} N; Y ^6' are C; and Y ^{3 'and} Y ^4' are independently CR ^5. For example, the compound of formula (I) in claim 9 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, which has the following structure Means:

Wherein R ^{9 is} independently halo, cyano, nitro, C ₃ -C ₈ cycloalkyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ halocycloalkyl , C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ Haloalkyl; R ¹ is halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-C ₁ -C ₄ alkyl, alkoxy-C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ haloalkenyl, C ₂ -C ₄ alkynyl, C ₂ -C ₄ haloalkynyl, C ₁ -C ₄ alkylcarbonyl, C ₁ -C ₄ haloalkyl Carbonyl, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₄ haloalkoxycarbonyl, aminocarbonyl, C ₁ -C ₄ alkylaminocarbonyl, C ₁ -C ₄ haloalkylaminocarbonyl, Di-C ₁ -C ₄ alkylaminocarbonyl, di-C ₁ -C ₆ haloalkylaminocarbonyl, optionally substituted 5 or 6 members containing 1 to 3 N, S or O heteroatoms heterocyclyl or -NR ^a R ^b, wherein R ^a and R ^b are independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; or R ^a and R ^b may be the nitrogen to which they are attached Together to form a 3-membered, 4-membered, 5-membered or 6-membered heterocyclic group, the heterocyclic group may include one to three additional heteroatoms selected from the group consisting of N, O and S and may be substituted as appropriate; R ⁵ is halogen Group, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, -SO _p (optionally substituted C _1- C ₆ alkyl or C ₁ -C ₆ haloalkyl), -SF ₅ or -NR ^c R ^d , wherein R ^c and ^{Rd are} independently H, C ₁ -C ₄ alkyl or C ₁ -C ₄ halo Alkyl; R ² is hydrogen or C ₁ -C ₃ alkyl; R ¹⁰ is hydrogen; D is -N- or -CH-, D ¹ is -NH-, -O-, -CH ₂ -; or D ¹ Bonded to a 2-membered to 5-membered chain containing N, O or S heteroatoms as appropriate to form spirocyclic heterocyclyl-heterocyclyl, spirocyclic heterocyclyl-carbocyclyl, spirocyclic carbocyclyl-carbon Cyclic or spirocyclic carbocyclyl-heterocyclic group; m is 0, 1, 2 or 3; and b is 0 or 1. For example, the compound of formula (I) of claim 12 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein R ¹ is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, C ₁ -C ₄ cycloalkyl, amino, C ₁ -C ₄ alkylamino, di(C ₁ -C ₄ alkyl)amino , N-morpholinyl, piperanyl, tetrahydropiperanyl or dihydropiperanyl; ^{each occurrence of R 4} is independently hydrogen, halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ cycloalkyl, or phenyl substituted 1 or 2 times by halo or C ₁ -C ₄ ^{alkyl as appropriate; and R 5} is independently at each occurrence Halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ cycloalkyl, or optionally substituted by halo or C ₁ -C ₄ alkyl for 1 or 2 times之phenyl. For example, the compound of formula (I) in claim 13 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein R ¹ is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, C ₁ -C ₄ cycloalkyl, amino, C ₁ -C ₄ alkylamino, di(C ₁ -C ₄ alkyl)amino , N-morpholinyl, piperanyl, tetrahydropiperanyl or dihydropiperanyl; ^{each occurrence of R 4} is independently hydrogen, halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ cycloalkyl, or phenyl substituted 1 or 2 times by halo or C ₁ -C ₄ ^{alkyl as appropriate; and R 5} is independently at each occurrence Halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ cycloalkyl, or optionally substituted by halo or C ₁ -C ₄ alkyl for 1 or 2 times之phenyl. Such as the compound of formula (I) of claim 17 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein R ¹ is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, C ₁ -C ₄ cycloalkyl, amino, C ₁ -C ₄ alkylamino, di(C ₁ -C ₄ alkyl)amino , N-morpholinyl, piperanyl, tetrahydropiperanyl or dihydropiperanyl; ^{each occurrence of R 4} is independently hydrogen, halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ cycloalkyl, or phenyl substituted 1 or 2 times by halo or C ₁ -C ₄ ^{alkyl as appropriate; and R 5} is independently at each occurrence Halogen, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ cycloalkyl, or optionally substituted by halo or C ₁ -C ₄ alkyl for 1 or 2 times之phenyl. For example, the compound of formula (I) of claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein Y Each of ¹ , Y ² and Y ^{3 is -CR 4} . For example, the compound of formula (I) of claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein Y ¹ is N; and Y ² and Y ³ are -CR ⁴ . For example, the compound of formula (I) of claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein Y ² is N; and Y ¹ and Y ³ are -CR ⁴ . For example, the compound of formula (I) of claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein Y ¹ and Y ³ are N; and Y ² is -CR ⁴ . For example, the compound of formula (I) of claim 1 or 2 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein Y ¹ and Y ² are N; and Y ³ is -CR ⁴ . For example, the compound of formula (I) of claim 1 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate, wherein the compound has the following table presents the structure wherein R ² and R ^{2 'both} are hydrogen; Q is oxygen; and the groups

It is abbreviated as "Ring System" in this table and represents the following groups:

Ring system A;

Ring system B;

Ring system C;

Ring system D;

Ring system E;

Ring system F;

Ring system G;

Ring system H;

Ring System I; and

Ring system K: Compound number Y ¹ Y ² Y ³ L X R ¹ R ³ Ring system 309 N CH CF L1 S i -Pr 3,5-Di-Cl-Ph A 264-0 CH N CH L1 S 2-OH-prop-2-yl 3,5-Di-Cl-Ph A 310 N CH CCl L1 S i -Pr 3,5-Di-F-Ph A 347 N CH CH L1 S i -Pr 2,3,5-Tri-F-Ph A 348 N CH CH L1 S i -Pr 2,3,5-Tri-F-Ph B 338 N CH CF L1 S t- Bu 3,5-Di-Cl-Ph B 336 N CH CF L1 S t- Bu 3,5-Di-Cl-Ph B 122 N CH CH L1 S

3,5-Di-F-Ph B 263-8 N CH CF L1 S 2-OH-prop-2-yl 3,5-Di-Cl-Ph A 263 N CH CF L1 S 2-F-prop-2-yl 3,5-Di-Cl-Ph A 210 N CH CH L1 S t- Bu 3,5-Di-F-Ph A 204 N CH CF L1 S i -Pr 3,5-Di-F-Ph A 211 N CH CH L1 S i -Pr 3,5-Di-Cl-Ph B 311 N CH CH L1 S 2-F-prop-2-yl 3,5-Di-F-Ph A 259-5 N CH CH L1 S 2-OH-prop-2-yl 3,5-Di-Cl-Ph B 257 N CH CH L1 S i -Pr 3,5-Di-F-Ph B 300 N CH CF L1 S 2-F-prop-2-yl 3,5-Di-F-Ph B 264 CH N CH L1 S 2-F-prop-2-yl 3,5-Di-Cl-Ph A 309 N CH CF L1 S i -Pr 3,5-Di-Cl-Ph A 259 N CH CH L1 S 2-F-prop-2-yl 3,5-Di-Cl-Ph B 285 N CH CH L1 S Prop-1-en-2-yl 3,5-Di-Cl-Ph A 260 N CH CF L1 S i -Pr 3,5-Di-F-Ph B 102 CH CH CH L1 S

3,5-Di-F-Ph A 212 N CH CH L1 S 2-F-prop-2-yl 3,5-Di-Cl-Ph A 119 N CH CH L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 120 N CH CH L1 S i -Pr 3,5-Di-F-Ph A 207 N CH CH L1 S i -Pr 3-F-Ph A 258 N CH CH L1 S i -Pr 3,5-Di-Cl-Ph B 212-0 N CH CH L1 S 2-OH-prop-2-yl 3,5-Di-Cl-Ph A 128 CH N CH L1 S i -Pr 3,5-Di-F-Ph A 337 N CH CF L1 S t- Bu 3,5-Di-F-Ph B 268-4 N CH CH L1 S 2-OH-prop-2-yl

A 234 N CH C-OMe L1 S i -Pr

A 254 N CH CH L1 S i -Pr 3,5-Di-F-Ph C 268 N CH CH L1 S 2-F-prop-2-yl

A 218 CH N CH L1 S i -Pr

A 220 N CH CH L1 S i -Pr

A 252 N CH CH L1 S i -Pr 3,5-Di-F-Ph D 209 N CH CH L1 S i -Pr 2,6-Di-F-Ph A 253 N CH CH L1 S i -Pr 3,5-Di-F-Ph E 246 N CH CH L1 S i -Pr

A 222 N CH CH L1 S i -Pr Cyclopentyl A 206 N CH CH L1 S i -Pr 2,3-bis-Cl-Ph A 255 N CH CH L1 S i -Pr

A 255-0 N CH CH L1 S i -Pr

A 203 N CH CH L1 S i -Pr 2,3,6-Tri-F-Ph A 256 N CH CH L1 S Prop-1-en-2-yl 3,5-Di-F-Ph B 302 N CH CH L1 S i -Pr -CF ₃ A 301 N CH CH L1 S i -Pr t -Bu A 238 N CH CH L1 S -CF ₂ CF ₃ 3,5-Di-F-Ph A 243 N CH CH L1 S i -Pr

A 213 N CH CH L1 S i -Pr

A 236 N CH CH L1 S -CF ₃ 3,5-Di-F-Ph A 201 N CH CH L1 S i -Pr 4-F-2,6-Di-Me-Ph A 199 N CH CH L1 S 2-OH-prop-2-yl 3,5-Di-F-Ph A 205 N CH CH L1 S -CHF ₂ 3,5-Di-F-Ph A 229 N CH CH L1 S i -Pr

A 223 N CH CH L1 S i -Pr Cyclohexyl A 224 N CH CH L1 S -N(CH ₃ ) ₂ Cyclohexyl A 115 N CH N L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 116 N CH N L1 S i -Pr 3,5-Di-F-Ph A 126 CH CH N L1 S

3,5-Di-F-Ph A 125 CH CH N L1 S -N(CH ₃ ) ₂ 3,5-Di-F-Ph A 127 CH N CH L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 129 CH N CH L1 S -N(CH ₃ ) ₂ 3,5-Di-F-Ph A 102-1 CH CH CH L1 S

3,5-Di-F-Ph A 101 CH CH CH L1 S

3,5-Di-F-Ph A 090 CH CH CH L1 S i -Pr 3,5-Di-F-Ph A 130 CH N CH L1 S

3,5-Di-F-Ph A 121 N CH CH L1 S -N(CH ₃ ) ₂ 3,5-Di-F-Ph A 026 CH CH CH L1 O i -Pr 3,5-Di-Cl-Ph A 029 CH CH CH L1 O i -Pr 2,6-Di-F-Ph A 030 C- i -Pr CH CH L1 O H 3,5-Di-Cl-Ph A 027 CH CH CH L1 O

3,5-Di-Cl-Ph A 098 CH CH C(3,5-Di-F-Ph) L1 S Prop-1-en-2-yl H A 100 CH CH C(3,5-Di-F-Ph) L1 S -N(CH ₃ ) ₂ H A 099 CH CH C(3,5-Di-F-Ph) L1 S i -Pr H A 28 CH CH CH L1 O i -Pr 3,5-Di-Cl-Ph F 92 CH CH CH L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 83 CH CH CH L1 S -N(CH ₃ ) ₂ 3,5-Di-F-Ph A 239-INT-1 N N CH L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 239 N N CH L1 S i -Pr 3,5-Di-F-Ph A 117 N CH N L1 S -N(CH ₃ ) ₂ 3,5-Di-F-Ph A 226-3 N CH CH L1 S -N(CH ₃ ) ₂ -C(O)CH ₃ A 259-4 N CH CH L1 S -C(O)CH ₃ 3,5-Di-Cl-Ph B 221 N CH CH L1 S i -Pr -CH(CH ₃ )CH ₂ -CH(CH ₃ ) ₂ A 319 N CH CF L2 S i -Pr 3,5-Di-Cl-Ph A 309 N CH CF L1 S i -Pr 3,5-Di-Cl-Ph A 115-INT-3 N CH N L1 S Br 3,5-Di-F-Ph A 237 N C-CF ₃ N L1 S i -Pr 3,5-Di-F-Ph A 225-0 N CH CH L1 S -N(CH ₃ ) ₂

A 226 N CH CH L1 S -N(CH ₃ ) ₂ -CH(CH ₃ )CH ₂ -CH(CH ₃ ) ₂ A 240 N CH CH L1 S i -Pr

A 241 N CH CH L1 S i -Pr

A 216 N CH CH L1 S

A 208 N CH CH L1 S i -Pr 2-Cl-6-F-Ph A 230 N CH CH L1 S -N(CH ₃ ) ₂

A 232 N CH CH L1 S i -Pr

A 228 N CH CH L1 S -N(CH ₃ ) ₂

A 250 N CH CH L1 S i -Pr

A 219 CH N CH L1 S i -Pr

A 262 N CH CH L1 S i -Pr 3,5-Di-F-Ph G 249 N CH CH L1 S i -Pr

A 247 N CH CH L1 S i -Pr

A 237 N C-CF ₃ N L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A 251 N CH CH L1 S i -Pr 3,5-Di-F-Ph H 215 N C-CF ₃ CH L1 S i -Pr 3,5-Di-Cl-Ph A 231 N CH CH L1 S i -Pr

A 225 N CH CH L1 S -N(CH ₃ ) ₂

A 253-0 N CH CH L1 S i -Pr 3,5-Di-F-Ph I 245 N CH CH L1 S i -Pr

A 214 N CH CH L1 S i -Pr

A 211-0 N CH CH L1 S i -Pr 3-Cl-5-(3,5-bis-Cl-Ph)-Ph A 248 N CH CH L1 S i -Pr

A 118 N CH N L1 S

3,5-Di-F-Ph A 202 N CH CH L1 S i -Pr 4-F-Ph A 242 N CH CH L1 S i -Pr

A 261 N CH CH L1 S i -Pr 3,5-Di-F-Ph K 217 N CH CH L1 S

A 227 N CH CH L1 S -N(CH ₃ ) ₂

A 124 CH CH N L1 S i -Pr 3,5-Di-F-Ph A 123 CH CH N L1 S Prop-1-en-2-yl 3,5-Di-F-Ph A . A veterinary composition comprising the compound of any one of claims 1 to 26 or a pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate Substances or solvates and veterinary acceptable carriers. A veterinary composition comprising the compound of any one of claims 1 to 26 or a pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate Substances or solvates, one or more other active agents, and veterinarily acceptable carriers. Use of a compound according to any one of claims 1 to 26 or its pharmaceutically or veterinarily acceptable salt, stereoisomer, tautomer, N-oxide, hydrate or solvate , Which is used to prepare medicaments for treating, controlling or preventing parasitic infection or infestation of animals.